WO2003068967A2 - Novel retina specific human proteins wdr17, net01, protein kinase a203, protein kinase mak a194, protein a105, protein a106 and c12orf3variants - Google Patents

Abstract

The present invention relates to nucleic acid molecules coding for proteins, isoforms of said proteins or mutant forms of said proteins whereby the level of expression of said proteins is connected with retinal diseases. Assessment of the expression level of proteins encoded by said nucleic acid molecules or corresponding mRNAs may be used for testing the predisposition of mammals and preferably humans of a retinal disease or for an acute state of such a disease. Preferred diseases in accordance with the invention are macular degeneration and more preferably AMD. The present invention further relates to methods of identifying compounds capable of normalizing the expression level of the aforementioned genes and of further genes affected by the abnormal expression. The identified compounds may be used for formulating compositions, preferably pharmaceutical compositions for preventing or treating retinal diseases. They may also be used as lead compounds for the development of medicaments having an improved efficiency, a longer half-life, a decreased toxicity etc. and to be employed in the treatment of retinal diseases. Included in the invention are also somatic gene therapy methods comprising the introduction of at least one functional copy of any of the above-mentioned genes into a suitable cell. Finally, the invention relates to non-human transgenic animals comprising at least one of the aforementioned genes in their germ line. The transgenic animals of the invention may be used for the development of medicaments for the treatment of retinal diseases. Finally, the present invention relates to diagnostic kits useful in the diagnosis of the aforementioned diseases.

Description

Novel retina specific human proteins WDR17, NET01, Protein Kinase A203, Protein Kinase AK A194, Protein A105, Protein

A106 and C12orf3variants

A variety of documents is cited throughout this specification. The disclosure content of said documents is herewith incorporated by reference.

SUMMARY OF THE INVENTION

The present invention relates to nucleic acid molecules coding for proteins, isoforms of said proteins or mutant forms of said proteins whereby the level of expression of said proteins is connected with retinal diseases. Assessment of the expression level of proteins encoded by said nucleic acid molecules or corresponding mRNAs may be used for testing the predisposition of mammals and preferably humans of a retinal disease or for an acute state of such a disease. Preferred diseases in accordance with the invention are nightblindness, macular degeneration and more preferably AMD. The present invention further relates to methods of identifying compounds capable of normalizing the expression level of the aforementioned genes and of further genes affected by the abnormal expression. The identified compounds may be used for formulating compositions, preferably pharmaceutical compositions for preventing or treating retinal diseases. They may also be used as lead compounds for the development of medicaments having an improved efficiency, a longer half-life, a decreased toxicity etc. and to be employed in the treatment of retinal diseases. Included in the invention are also somatic gene therapy methods comprising the introduction of at least one functional copy of any of the above-mentioned genes into a suitable cell. Finally, the invention relates to non-human transgenic animals comprising at least one of the aforementioned genes in their germ line. The transgenic animals of the invention may be used for the development of medicaments for the treatment of retinal diseases. Finally, the present invention relates to diagnostic kits useful in the diagnosis of the aforementioned diseases.

BACKGROUND OF THE INVENTION

The human retina is a multilayered tissue composed of number of distinct cell types that are highly specialized in their function to transform light energy into electric impulses and to further transmit these signals to the brain where they are processed and perceived as vision. Numerous active genes are required to perform and control the phototransduction process and also to establish and maintain the structure and integrity of the various components of the retinal tissue. As a consequence, this unique and highly evolved system may be especially susceptible to various genetic defects, thus leading to a wide range of retinal disease phenotypes. In contrast to the Chorioretinitis and the Herpesretinitis, which can be considered as acquired forms of retinal diseases, the majority of retinal disorders are reduced to a genetic predisposition: e.g. Ablatio retinae, Retinoblastoma, Astrocytome of the retina, Angiomatosis retinae, Coat's disease (Retinitis exsudativa), Eale's disease, Retinopathia centralis serosa, Oculary albinism, Retinitis pigmentosa, Retinitis punctata albescens, Ushers syndrome, Congenital amaurosis, Cone dystrophy, Best vitelliform macular dystrophy (Morbus Best), X-linked juvenile retinoschisis, North Carolina macular dystrophy, Sorsby fundus dystrophy, Doyne honeycomb retinal dystrophy/Malattia leventinese, Stargardt disease (Morbus Stargardt), Wagner's vitreoretinal degeneration or Age- related macular degeneration (AMD).

Considering the impressive advances in the single-gene retinopathies like Morbus Best or Morbus Stargardt, less progress has been made in deciphering the molecular mechanisms underlying the etiology of the age-related macular degeneration (AMD).

Age-related macular degeneration (AMD), which can be thought as a sub-type of retinal degeneration, is the most common cause of visual morbidity in the developed world with a prevalence increasing from 9% in persons over 52 years to more than 25% in persons over the age of 75 (Paetkau et al. 1978, Leibowitz et al. 1980, Banks and Hutton 1981 , Ghafour et al. 1983, Hyman 1987, Hyman et al. 1983, Grey et al. 1989, Yap and Weatherill 1989, Heiba et al. 1994).

An early stage in the evolution of AMD pathology is accompagnied by an increasing accumulation of yellowish lipofuscin-like particles within the retinal pigment epithelium (RPE; Feeney 1978). It is thought that these particles represent remnants of undigested phagocytosed photoreceptor outer segment membranes which, in the normal process, are excreted basally through Bruch's membrane into the choriocapillaris. Over time, accumulation of lipofuscin-like particles affect Bruch's membrane and lead to its progressive destruction (Hogan and Alvarado 1967, Sarks 1976, Feeney-Burns and Ellersieck 1985, Pauleikhoff et al. 1990). The deposits in the RPE and Bruch's membrane consists largely of lipids although their exact composition may vary between individuals with some deposits revealing more polar phospholipids while others contain predominantly apolar neutral lipids.

These individual differences in drusen composition are thought to be the basis for the clinical heterogeneity in AMD (Green et al. 1985). While some patients present with an ingrowth of vessels from the choriocapillaris through Bruch's membrane (neovascularization) (Bressler et al. 1982), others show pigment epithelial detachment due to excudation underneath the RPE (Gass 1967, Green et al. 1985), and a third group of patients experiences a slow decrease of visual loss due to atrophic changes in the RPE and the overlying sensory neuroretina (Maguire and Vine 1986). Although much less common the excudative/neovascular form of AMD accounts for more than 80% of blindness with a visual acuity of < 20/200 (Bressler et al. 1988).

AMD is a complex disease caused by exogenous as well as endogenous factors (Meyers and Zachary 1988; Seddon et al. 1997). In addition to environmental factors, several personal risk factors such as hypermetropia, light skin and iris colour, elevated serum cholesterol levels, hypertension or cigarette smoking have been suggested (Hyman et al. 1983, Klein et al. 1993, Sperduto and Hiller 1986, The Eye Disease Case-Control Study Group 1992, Bressler and Bressler 1995). A genetic component for AMD has been documented by several groups (Gass 1973, Piguet et al. 1993, Silvestri et al. 1994) and has lead to the hypothesis that the disease may be triggered by environmental/individual factors in those persons who are genetically predisposed. The number of genes which, when mutated, can confer susceptibility to AMD is not known but may be numerous. The late onset of symptoms generally in the 7th decade of life as well as the clinical and likely genetic heterogeneity make it difficult to apply conventional approaches for the identification of genes predisposing to AMD.

The molecular basis of the aforementioned retinal diseases has so far not been elucidated. Consequently, medicaments available on the market are suitable to treat the symptoms of such diseases only. Accordingly, the technical problem underlying the present invention was to provide means and methods for the specific intervention in retinal diseases at the molecular level.

The solution to said technical problem is achieved by providing the embodiments characterized in the claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a nucleic acid molecule comprising a nucleotide sequence selected form the group consisting of:

(a) a nucleotide sequence encoding the preferably mature form of a protein comprising the amino acid sequence as depicted in figure 4 or of a precursor thereof;

(b) a nucleotide sequence comprising of the DNA sequence as depicted in figure 3;

(c) a nucleotide sequence hybridizing with the complementary strand of a nucleotide sequence as defined in (a) or (b) under stringent hybridization conditions and coding for a (poly)peptide having the same function as the (poly)peptide having the amino acid sequence depicted in 4;

(d) a nucleotide sequence encoding a polypeptide derived from the (poly)peptide encoded by a nucleotide sequence of (a) or (b) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (a) or (b), whereby said (poly)peptide has the same function as the (poly)peptide having the amino acid sequence depicted in figure 4;

(e) a nucleotide sequence encoding a protein having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (a) or (b), whereby said (poly)peptide has the same function as the (poly)peptide having the amino acid sequence depicted in figure 4; (f) a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (a) or (b) and encoding a (poly)peptide having the same function as the (poly)peptide having the amino acid sequence depicted in figure 4; (g) a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (a) or (b) and encoding a (poly)peptide having the same function as the (poly)peptide having the amino acid sequence depicted in figure 4; and

(h) a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of (a) to (g) ;

Preferably, the nucleic acid molecule of the invention is obtained from human sources. The term "mature form of the protein" defines in the context of the present invention a protein translated from its corresponding mRNA and optionally subsequently modified. The mature form of a protein would not contain a leader sequence. A leader sequence, on the other hand, would be regarded as contained in the definition of the "precursor".

By the term "(poly)peptide" as used herein molecules are defined which comprise the group of peptides, consisting of up to 30 amino acids, as well as the group of polypeptides, consisting of more than 30 amino acids. Thus, by the group of polypeptides makromolecules are comprised which are also designated in accordance with the invention, as proteins. Specific examples of a protein, in case of catalyzing an chemical reaction, include enzymes. The term "hybridizing" as used herein refers to a pairing of polynucleotides to a complementary strand of polynucleotide which thereby form a hybrid. Said complementary strand polynucleotides are, e.g. the polynucleotides of the invention or parts thereof. Therefore, said polynucleotides may be useful as probes in Northern or Southern Blot analysis of RNA or DNA preparations, respectively, or can be used as oligonucleotide primers in PCR analysis dependent on their respective size. Preferably, said hybridizing polynucleotides comprise at least 10, more preferably at least 15 nucleotides in length while a hybridizing polynucleotide of the present invention to be used as a probe preferably comprises at least 100, more preferably at least 200, or most preferably at least 500 nucleotides in length. It is well known in the art how to perform hybridization experiments with nucleic acid molecules, i.e. the person skilled in the art knows what hybridization conditions s/he has to use in accordance with the present invention. Such hybridization conditions are referred to in standard text books such as "Molecular Cloning A Laboratory Manual", Cold Spring Harbor Laboratory (1989) N.Y. or Higgins, S.J., Hames, D. "RNA Processing: A practical approach", Oxford University Press (1994), Vol. 1 and 2.

"Stringent hybridization conditions" refers to conditions which comprise, e.g. an overnight incubation at 42°C in a solution comprising 50% formamide, 5x SSC (750 mM NaCl, 75 mM sodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulfate, and 20 μg/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1 x SSC at about 65°C. Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the invention at lower stringency hybridization conditions. Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency); salt conditions, or temperature. For example, lower stringency conditions include an overnight incubation at 37°C in a solution comprising 6X SSPE (20X SSPE = 3M NaCl; 0.2M NaH₂PO4; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 μg/ml salmon sperm blocking DNA; followed by washes at 50°C with 1 X SSPE, 0.1% SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X SSC). Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility. Preferred in accordance with the present inventions are polynucleotides which are capable of hybridizing to the polynucleotides of the invention or parts thereof, under stringent hybridization conditions, i.e. which do not cross hybridize to unrelated polynucleotides. The nucleic acid molecules that are homologous to the above-described molecules and that represent derivatives of these molecules usually are variations of these molecules that represent modifications having the same biological function. They can be naturally occurring variations, for example sequences from other organisms, or mutations that can either occur naturally or that have been introduced by specific mutagenesis. Furthermore, the variations can be synthetically produced sequences. The allelic variants can be either naturally occurring variants or synthetically produced variants or variants produced by recombinant DNA processes. Generally, by means of conventional molecular biological processes it is possible (see, e.g., Sambrook et al., 1989) to introduce different mutations into the nucleic acid molecules of the invention. One possibility is the production of deletion mutants in which nucleic acid molecules are produced by continuous deletions from the 5'- or 3'-terminus of the coding DNA sequence and that lead to the synthesis of proteins that are shortened accordingly. Another possibility is the introduction of single-point mutation at positions where a modification of the amino acid sequence influences, e.g., the enzyme activity or the regulation of the enzyme. By this method muteins can be produced, for example, that possess a modified K_m-value or that are no longer subject to the regulation mechanisms that normally exist in the cell, e.g. with regard to allosteric regulation or covalent modification. Such muteins may be identified, e.g. by methods of the present invention, to be valuable as therapeutically useful modulators (inhibitors/antagonists or enhancer/agonists) of the activity of the proteins of the present invention.

Nucleic acid molecules that hybridize to the molecules of the invention can be isolated, e.g., from genomic or cDNA libraries that were produced from human cell lines or tissues. In order to identify and isolate such nucleic acid molecules the molecules of the invention or parts of these molecules or the reverse complements of these molecules can be used, for example by means of hybridization according to conventional methods (see, e.g., Sambrook et al., 1989). As a hybridization probe nucleic acid molecules can be used, for example, that have exactly or basically the nucleotide sequence depicted in any of figures 1 , 3, 5, 7, 9, 11 or 13 or parts of these sequences or sequences complementary thereto. The fragments used as hybridization probe can be synthetic fragments that were produced by means of conventional synthesis methods and the sequence of which basically corresponds to the sequence of a nucleic acid molecule of the invention. The genes described herein coding for the proteins of the invention and isoforms (isogenes) and mutant forms of said proteins are causally involved in the etiology of AMD, nightblindness and other retinal diseases as they are (abnormally) expressed in retinal tissue and not in other tissues tested. The identification of said genes was achieved by the use of a new computer-assisted strategy which aimed at the genome-wide identification of genes that are expressed exclusively or predominantly in the human retina and made use of the in silico expression information enclosed in the expressed sequence tag (EST) clusters of the publicly available UniGene dataset (Schuler, 1997). Preliminary mutational analyses in patients with AMD have resulted, i.e. in the identification of mutations in the WDR17 gene and the NETO1 gene the identification of which are •• described exemplarily in the appended examples. Identification of the other nucleic acid molecules of the invention was carried out in an analogous manner. Moreover, functions and potential functions of the proteins encoded by the described nucleic acid molecules have been identified. In particular, protein kinase MAK A194 and protein kinase A203 are characterized to have kinase activity (serine/threonine-protein kinases). Protein kinase MAK A194 shows homology to the murine MAK Q04859 and protein kinase A203 to the Homo sapines similar to serine/threonine kinase 35.

Interaction studies have revealed a number of interaction partners in the yeast two- hybrid system for the variants of Protein kinase MAK A194: JEM-1 : homo sapiens basic leucine zipper nuclear factor 1 (variant 2, variant 3 and variant 4), homo sapiens myomegalin (variant 3), TSG101 : homo sapiens tumor susceptibility protein 1 (variant 3), KIF1 B: homo sapiens kinesin-like protein 1 B (variant 3 and variant 4), NXP2: homo sapiens nuclear matrix protein 2 (variant 3), BtRP1 : bos taurus retinitis pigmentosa 1 protein (variant 3), ATIP1 : homo sapiens AT2 receptor interacting protein 1 (variant 3), SCOCO: homo sapiens short coiled coil protein (variant 3), homo sapiens similar to p75NTR associated cell death executor (variant 3), homo sapiens similar to thyroid hormone receptor coactivator (variant 4). The interaction of variant 3 of Protein kinase MAK A194 with a homolog of human RP-1 is expected to be of particular relevance since a mutant form of RP-1 has been associated with the onset of Retinitis Pigmentosa. Therefore, this experimental observation strongly suggests that non-functional mutants of Protein kinase MAK A194 or mutants of Protein kinase MAK A194 which are impaired in their interaction with RP-1 is expected to be associated with retinal diseases, in particular with Retinitis Pigmentosa.

WDR17, protein A105 and protein A106 have similar functions as the Homo sapiens similar of hypothetical protein LOC166736, Homo sapiens hypothetical protein DKFZp761D221 and Homo sapiens hypothetical protein FLJ 13993. The identified nucleotide sequence of C12orf3vanriants shows homology to Homo sapiens chromosome 12 open reading frame and nucleotide sequence of the NET01 possesses homology to Homo sapiens chromosome 18 clone RP11676J15 map 18q22 (30 unordered pieces). Surprisingly expression of the (poly)peptides encoded by the nucleic acid molecules depicted in figures 1 , 3, 5, 7, 9, 11 and 13 has been demonstrated in retinal tissue. Interaction studies have revealed a number of interaction partners in the yeast two- hybrid system for the variants of Protein A105: Variants 1 , 4, 5, 7 and 8 have been shown to interact with a protein with significant homology to sus scrofa secreted neuronal protein and endocrine protein (7B2), the human homolog of which is expected to be involved in proteolytic degradation in cells of the retina. Therefore, 7B2-mediated impaired protein degradation is expected to be involved in the onset of AMD. In addition, variant 1 has been shown to interact with three other proteins: WAC, homo sapiens WW domain-containing adapter wit a coiled-coil region, isoform 1 ; Homo sapiens C20orf43 and btATP1B2. Particularly relevant is btATP1B2, the β2-subunit of NA/KA-ATPase, the murine homolog of which has been demonstrated to be crucial for photoreceptor function. Moreover, studies with variant 6 of Protein A105 in the yeast two-hybrid system demonstrate a number of interaction partners: Homo sapiens similar to DKFZP566B183 protein, Homo sapiens voltage-dependent anion channel 3 and Mus musculus similar to calcium channel, voltage-dependent, α1F-subunit (homolog of human protein CACNA1F). The interaction with the α1F-subunit of a voltage-dependent calcium-channel is expected to be of particular relevance since its human homolog has been shown to be involved in certain forms of X-linked nightblindness. In summary, these experimental observations strongly suggests that non-functional mutants of Protein A105 or mutants of Protein A105 which are impaired in their interaction with the NA/KA-ATPase are likely to be associated with retinal diseases.

The term "isoform" means, in connection with the term "gene" or "nucleic acid", a form of a gene or nucleic acid including a derivative of a gene or nucleic acid resulting from alternative splicing, alternative polyadenylation, alternative promoter usage or RNA editing. Isoforms can be detected by

(a) in silico analysis (e.g. by clustering analysis of any types of expressed sequences or the corresponding proteins, by alignment of expressed sequences with chromosomal DNA, by interspecies comparisons or by analysis of the coding as well as non-coding sequences like promoters or regulatory RNA processing sites for SNPs or known mutations causing a disease). (b) any type of hybridisation techniques (e.g. Northern blots, nuclease protection assays, microarrays) starting from RNA (as described in Higgins,

S.J., Hames, D. loc. cit.; Sambrook, loc. cit.). (c) PCR-applications as well as hybridisation techniques starting from single strand or double strand cDNA obtained by reverse transcription, as described for example in Stoss, O., Stoilov, P., Hartmann, A.M., Nayler, O.,

Stamm, S. The in vivo minigene approach to analyse tissue-specific splicing.

Brain Res. Brain Res. Protoc. (1999), 3:383-394. Isoforms of proteins/(po!y)peptides are preferably encoded by said isoforms of genes/nucleic acids. Primers/probes for RT-PCR or hybridisation techniques are designed in a fashion that at least one of the primers/probes specifically recognizes one isoform. If differences in the molecular weight of isoforms are large enough to separate them by electrophoretic or chromatographic methods, it is also possible to detect multiple isoforms at once by employing primers/probes that flank the spliced regions. The isoforms are then sequenced and analysed as described in a).

The term "isogenes" is used herein to describe genes that are considered to be generated by gene duplication. They can be identified by comparing the homology of the DNA-, RNA-, or protein-sequence of interest with other DNA, RNA or protein-sequences of the same species. There might be strong differences in the degree of homology between isogenes of the same species. This may be dependent on the time-point, when the gene duplication event took place in evolution and the degree of conservation during evolution.

Isogenes can be identified and cloned by RT-PCR as has been demonstrated by Screaton et al. (1995) EMBO J. 14:4336-4349 or Huang et al. (1998) Gene 211 : 49-55. Isogenes can also be identified and cloned by colony hybridization or plaque hybridization as described in Sambrook, loc. cit.. In a first step, either a genomic or a cDNA library e.g. in bacteria or phages is generated. In order to identify isogenes, colony hybridization or plaque hybridization is slightly modified in a way that cross-hybridizations are detectable under conditions of lower stringency. This can be achieved by lowering the calculated temperature for hybridization and washing and/or by lowering the salt concentration of the washing solutions (Sambrook, loc. cit.). For example, a low-stringency washing condition may include 2 washing steps at a temperature between 45°C and 65°C with 4xSSC, 0,1% SDS for 30 min (50 ml) and finally two washing steps at room temperature with 50 ml of a solution containing 2xSSC, 0.1 % SDS for 30 min. After detection, signal intensity of colonies containing an isogene is dependent on the homology of a gene and its isogene(s).

The aforementioned nucleic acid molecules may be isolated from samples of tissues or cells. According to the understanding of a person skilled in the art the term "isolated nucleic acid molecule" includes nucleic acid molecules substantially free of other nucleic acids, proteins, lipids, carbohydrates or other materials with which it is naturally associated. For example, an isolated nucleic acid molecule could be part of a vector or a composition of matter, or could be contained within a cell, and still be "isolated" because that vector, composition of matter, or particular cell is not the original environment of the nucleic acid molecule. The proteins encoded by the various variants of the nucleic acid molecules of the invention show certain characteristics, such as enzyme activity, molecular weight, immunological reactivity or conformation or physical properties like the electrophoretical mobility, chromatographic behavior, sedimentation coefficients, solubility, spectroscopic properties, stability; pH optimum, temperature optimum. Thus, said proteins can be unambiguously identified by a person skilled in the art. A preferred embodiment of the invention relates to a nucleic acid molecule of at least 15 nucleotides in length hybridizing specifically an above described nucleic acid molecule or with a complementary strand thereof.

Specific hybridization occurs preferably under stringent conditions and implies no or very little cross-hybridization with nucleotide sequences encoding no or substantially different proteins. Such nucleic acid molecules may be used as probes and/or for the control of gene expression. Nucleic acid probe technology is well known to those skilled in the art who will readily appreciate that such probes may vary in length. Preferred are nucleic acid probes of 17 to 35 nucleotides in length. Of course, it may also be appropriate to use nucleic acids of up to 100 and more nucleotides in length. The nucleic acid probes of the invention are useful for various applications. On the one hand, they may be used as PCR primers for amplification of nucleic acid molecules according to the invention or for detecting mutations within said nucleic acid molecules. Another application is the use as a hybridization probe to identify polynucleotides hybridizing to the nucleic acid molecules of the invention by homology screening of genomic DNA libraries. Nucleic acid molecules according to this preferred embodiment of the invention which are complementary to a nucleic acid molecule as described above may also be used for the repression of expression of a gene comprising such a nucleic acid molecule, for example due to an antisense or triple helix effect or the RNAi technology (see, e.g. Zamore Nat Struct Biol 2001 , 8(9):746-50 or Tuschl T. CHEMBIOCHEM. 2001 , 2:239-245) or for the construction of appropriate ribozymes (see, e.g., EP-B1 0 291 533, EP-A1 0 321 201, EP-A2 0 360 257) which specifically cleave the (pre)-mRNA of a gene comprising a nucleic acid molecule of the invention. The techniques underlying said repression of expression are well known in the art. Selection of appropriate target sites and corresponding ribozymes can be done as described for example in Steinecke, Galbraith et al. (1995). Standard methods relating to antisense technology have also been described (Melani et al., 1991). Said nucleic acid molecules may be chemically synthesized or transcribed by an appropriate vector containing a chimeric gene which allows for the transcription of said nucleic acid molecule in the cell. Such nucleic acid molecules may further contain ribozyme sequences as described above. The present invention also relates to (i) an antisense RNA sequence characterized in that it is complementary to an mRNA transcribed from a nucleic acid molecule of the present invention or a part thereof and can selectively bind to said mRNA, said sequence being capable of inhibiting the synthesis of the protein encoded by said nucleic acid molecules, and (ii) a ribozyme characterized in that it is complementary to an mRNA transcribed from a nucleic acid molecule of the present invention or a part thereof and can selectively bind to and cleave said mRNA, thus inhibiting the synthesis of the proteins encoded by said nucleic acid molecules. Preferably, the antisense RNA and ribozyme of the invention are complementary to the coding region of the mRNA, e.g. to the 5' part of the coding region. The person skilled in the art provided with the sequences of the nucleic acid molecules of the present invention will be in a position to produce and utilize the above described antisense RNAs or ribozymes.

It is also to be understood that the nucleic acid molecules of the invention can be used for „gene targeting" and/or "gene replacement", for restoring a mutant gene or for creating a mutant gene via homologous recombination; see for example Le Mouellic et al. (1990) or Joyner (1999). Furthermore, the person skilled in the art is well aware that it is also possible to label such a nucleic acid probe with an appropriate marker for specific applications, such as for the detection of the presence of a nucleic acid molecule of the invention in a sample derived from an organism, in particular mammals, preferably human. A number of companies such as Pharmacia Biotech (Piscataway NJ), Promega (Madison Wl), and US Biochemical Corp (Cleveland OH) supply commercial kits and protocols for these procedures. Suitable reporter molecules or labels include those radionuclides, enzymes, fluorescent, chemoluminescent, or chromogenic agents as well as substrates, cofactors, inhibitors, magnetic particles and the like. Patents teaching the use of such labels include US Patents US-A- 3,817,837; US-A-3,850,752; US-A-3,939,350; US-A-3,996,345; US-A-4,227,437; US-A-4,275,149 and US-A-4, 366,241.

Furthermore, the so-called "peptide nucleic acid" (PNA) technique can be used for the detection or inhibition of the expression of a nucleic acid molecule of the invention. For example, the binding of PNAs to complementary as well as various single stranded RNA and DNA nucleic acid molecules can be systematically investigated using thermal denaturation and BIAcore surface-interaction techniques (Jensen et al., 1997). Further, the nucleic acid molecules described above as well as PNAs derived therefrom can be used for detecting point mutations by hybridization with nucleic acids obtained from a sample with an affinity sensor, such as BIAcore (Gotoh et al., 1997). Hybridization based DNA screening on peptide nucleic acids (PNA) oligomer arrays are described in the prior art (e.g. Weiler et al., 1997). The synthesis of PNAs can be performed according to methods known in the art, for example, as described in Koch et al. (1997) and Finn et al., 1996. Further possible applications of such PNAs, for example as restriction enzymes or as templates for the synthesis of nucleic acid oligonucleotides are known to the person skilled in the art and are, for example, described in Veselkov et al. (1996) and Bohler et al. (1995).

Moreover, the nucleic acid molecules of the invention can be used for mapping sequences to chromosomes by preparing PCR primers (preferably 15-25 bp) from the sequences of the invention. Primers may be selected according to the knowledge of a person skilled in the art by using computer analysis so that primers do not span more than one predicted exon in the genomic DNA. Moreover, sublocalization of genes described herein can be achieved with panels of specific chromosome fragments. Other gene mapping strategies that can be used include in situ hybridization, prescreening with labeled flow-sorted chromosomes, and preselection by hybridization to construct chromosome specific cDNA libraries. Precise chromosomal location of the genes can also be achieved using fluorescence in situ hybridization (FISH) of a metaphase chromosomal spread. This technique uses polynucleotides as short as 500 or 600 bases; however, polynucleotides comprising 1 ,000-4,000 bp are preferred. For a review of this technique, see Verma and Babu (1988). For chromosome mapping, the nucleic acid molecules of the invention can be used individually (to mark a single chromosome or a single site on that chromosome) or in panels (for marking multiple sites and/or multiple chromosomes). Preferred nucleic acid molecules correspond to the noncoding regions of the cDNAs because the coding sequences are more likely conserved within gene families, thus increasing the chance of cross hybridization during chromosomal mapping. Once a gene has been mapped to a precise chromosomal location, the physical position of the gene can be used in linkage analysis. Linkage analysis establishes co- inheritance between a chromosomal location and presentation of the disease. Thus, once co-inheritance is established, differences in the gene(s) between affected and unaffected individuals can be examined. First, visible structural alterations in the chromosomes, such as deletions or translocations, are examined in chromosome spreads, or by PCR. If no structural alterations exist, the presence of point mutations are ascertained. Mutations observed in some or all affected individuals, but not in normal individuals, indicate that the mutation may cause the disease. However, complete sequencing of the polypeptides and the corresponding genes from several normal individuals might be required to distinguish the mutation from a polymorphism. If a new polymorphism is identified, this polymorphic polypeptide can be used for further linkage analysis.

An alternative embodiment of the invention relates to a vector comprising an above defined nucleic acid molecule. A preferred embodiment relates to a vector, wherein the nucleic acid molecule is DNA.

The vector of the present invention may be, e.g., a plasmid, cosmid, virus, bacteriophage or another vector used e.g. conventionally in genetic engineering, and may comprise further genes such as marker genes which allow for the selection of said vector in a suitable host cell and under suitable conditions.

Furthermore, the vector of the present invention may, in addition to the nucleic acid sequences of the invention, comprise expression control elements, allowing proper expression of the coding regions in suitable hosts. Such control elements are known to the artisan and may include a prompter, a splice cassette, translation initiation codon, translation and insertion site for introducing an insert into the vector. Preferably, the nucleic acid molecule of the invention is operatively linked to said expression control sequences allowing expression in eukaryotic or prokaryotic cells. Furthermore, the nucleic acid molecules of the invention can be employed in recombinant hosts or vectors or viruses, (poly)peptides of the invention can be expressed by or in recombinant hosts or vectors or viruses and recombinant hosts or vectors or viruses of the invention can be generated and employed as in or in a manner analogous to the methods for making and/or using and/or administering a vector, either in vivo or in vitro, see e.g., U.S. Patent Nos. 4,603,112, 4,769,330, 5,174,993, 5,505,941 , 5,338,683, 5,494,807, 4,722,848, 5,942,335, 5,364,773, 5,762,938, 5,770,212, 5,942,235, 5,756,103, 5,766,599, 6,004,777, 5,990,091 , 6,033,904, 5,869,312, 5,382,425, WO 94/16716 or WO 96/39491. Many suitable vectors are known to those skilled in molecular biology, the choice of which would depend on the function desired and include plasmids, cosmids, viruses, bacteriophages and other vectors used conventionally in genetic engineering. Methods which are well known to those skilled in the art can be used to construct various plasmids and vectors; see, for example, the techniques described in Sambrook loc.cit, and Ausubel, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. (1989), (1994). Alternatively, the polynucleotides and vectors of the invention can be reconstituted into liposomes for delivery to target cells. As discussed in further details below, a cloning vector was used to isolate individual sequences of DNA. Relevant sequences can be transferred into expression vectors where expression of a particular (poly)peptide is required. Typical cloning vectors include pBscpt sk, pGEM, pUC9, pBR322 and pGBT9. Typical expression vectors include pTRE, pCAL-n-EK, pESP-1 , pOP13CAT.

Hence, in a preferred embodiment of the present invention the above-described vector is in accordance with one preferred embodiment of the invention an expression vector wherein said nucleic acid molecule is operatively linked to one or more expression control sequences allowing the transcription and optionally translation in prokaryotic and/or eukaryotic host cells.

An "expression vector" is a construct that can be used to transform a selected host cell and provides for expression of a coding sequence in the selected host. Expression vectors can for instance be cloning vectors, binary vectors or integrating vectors. Expression comprises transcription of the nucleic acid molecule preferably into a translatable mRNA. Regulatory elements ensuring expression in prokaryotic and/or eukaryotic cells are well known to those skilled in the art. In the case of eukaryotic cells they comprise normally promoters ensuring initiation of transcription and optionally poly_^-A signals ensuring termination of transcription and stabilization of the transcript. Possible regulatory elements permitting expression in prokaryotic host cells comprise, e.g., the PL, lac, trp or tac promoter in E. coli, and examples of regulatory elements permitting expression in eukaryotic host cells are the AOX1 or GAL1 promoter in yeast or the CMV-, SV40-, RSV-promoter (Rous sarcoma virus), CMV-enhancer, SV40-enhancer or a globin intron in mammalian and other animal cells. In this context, suitable expression vectors are known in the art such as Okayama-Berg cDNA expression vector pcDV1 (Pharmacia), pCDMδ, pRc/CMV, pcDNAI , pcDNA3 (In-vitrogene), pSPORTI (GIBCO BRL). An alternative expression system which could be used to express a cell cycle interacting protein is an insect system. In one such system, Autographa californica nuclear polyhedrosis virus (AcNPV) is used as a vector to express foreign genes in Spodoptera frugiperda cells or in Trichoplusia larvae. The coding sequence of a nucleic acid molecule of the invention may be cloned into a nonessential region of the virus, such as the polyhedrin gene, and placed under control of the polyhedrin promoter. Successful insertion of said coding sequence will render the polyhedrin gene inactive and produce recombinant virus lacking coat protein coat. The recombinant viruses are then used to infect S. frugiperda cells or Trichoplusia larvae in which the protein of the invention is expressed (Smith, J. Virol. 46 (1983), 584; Engelhard, Proc. Nat. Acad. Sci. USA 91 (1994), 3224-3227).

The term "control sequence" refers to regulatory DNA sequences which are necessary to effect the expression of coding sequences to which they are ligated. The nature of such control sequences differs depending upon the host organism. In prokaryotes, control sequences generally include promoter, ribosomal binding site, and terminators. In eukaryotes generally control sequences include promoters, terminators and, in some instances, enhancers, transactivators or transcription factors. The term "control sequence" is intended to include, at a minimum, all components the presence of which is necessary for expression, and may also include additional advantageous components. Possible regulatory elements permitting expression in for example mammalian host cells comprise the CMV- HSV thymidine kinase promoter, SV40, RSV-promoter (Rous sarcome virus), human elongation factor 1 -promoter, aPM-l promoter (Schaffer, Biochem. Biophys. Res. Commun. 260 (1999), 416-425), or inducible promoter(s), like, metallothionein or tetracyclin promoter, or enhancers, like CMV enhancer or SV40- enhancer. For the expression in prokaryotic cells, a multitude of promoters including, for example, the tac-lac-promoter or the trp promoter, has been described. Besides elements which are responsible for the initiation of transcription such regulatory elements may also comprise transcription termination signals, such as SV40-poly-A site or the tk-poly-A site, downstream of the polynucleotide. In this context, suitable expression vectors are known in the art such as Okayama-Berg cDNA expression vector pcDV1 (Pharmacia), pRc/CMV, pcDNAI , pcDNA3 (In- vitrogene), pSPORTI (GIBCO BRL), Casper, Casper-HS43, pUAST, or prokaryotic expression vectors, such as lambda gt11. Beside the nucleic acid molecules of the present invention, the vector may further comprise nucleic acid sequences encoding secretion signals. Such sequences are well known to the person skilled in the art. Furthermore, depending on the expression system used leader sequences capable of directing the (poly)peptide to a cellular compartment may be added to the coding sequence of the nucleic acid molecules such leader sequences are well known in the art. The leader sequence(s) is (are) assembled in appropriate phase with translation, initiation and termination sequences, and preferably, a leader sequence capable of directing secretion of translated protein, or a protein thereof, into the periplasmic space or extracellular medium. Optionally, the heterologous sequence can encode a fusionprotein including an C- or N- terminal identification peptide imparting desired characteristics, e.g., stabilization or simplified purification of the expressed recombinant product. Once the vector has been incorporated into the appropriate host, the host is maintained under conditions suitable for high level expression of the nucleotide sequences (e.g. by antibiotic selection), and, as desired, the collection and purification of the complex of the invention or its individual (poly)peptide(s) or fragments thereof may follow. The term "operably linked" refers to a juxtaposition wherein the components so described are in a relationship permitting them to function in their intended manner. A control sequence "operably linked" to a coding sequence is ligated in such a way that expression of the coding sequence is achieved under conditions compatible with the control sequences. In case the control sequence is a promoter, it is obvious for a skilled person that double-stranded nucleic acid is preferably used. In plants, promoters commonly used are the polyubiquitin promoter, and the actin promoter for ubiquitous expression. The termination signals usually employed are from the Nopaline Synthase promoter or from the CAMV 35S promoter. A plant translational enhancer often used is the TMV omega sequences, the inclusion of an intron (lntron-1 from the Shrunken gene of maize, for example) has been shown to increase expression levels by up to 100-fold. (Mait, Transgenic Research 6 (1997), 143-156; Ni, Plant Journal 7 (1995), 661-676). Additional regulatory elements may include transcriptional as well as translational enhancers. Furthermore, the vector of the present invention may also be a gene transfer or gene targeting vector. Gene therapy, which is based on introducing therapeutic genes into cells by ex-vivo or in-vivo techniques is one of the most important applications of gene transfer. Suitable vectors, methods or gene-delivering systems for in-vitro or in-vivo gene therapy are described in the literature and are known to the person skilled in the art; see, e.g., Giordano, Nature Medicine 2 (1996), 534-539; Schaper, Circ. Res. 79 (1996), 911-919; Anderson, Science 256 (1992), 808-813, Isner, Lancet 348 (1996), 370-374; Muhlhauser, Circ. Res. 77 (1995), 1077-1086; Onodua, Blood 91 (1998), 30-36; Verzeletti, Hum. Gene Ther. 9 (1998), 2243-2251 ; Verma, Nature 389 (1997), 239-242; Anderson, Nature 392 (Supp. 1998), 25-30; Wang, Gene Therapy 4 (1997), 393-400; Wang, Nature Medicine 2 (1996), 714-716; WO 94/29469; WO 97/00957; US 5,580,859; US 5,589,466; US 4,394,448 or Schaper, Current Opinion in Biotechnology 7 (1996), 635-640, and references cited therein. In particular, specific vectors for use in retinal cells are described by DiPolo (Proc Natl Acad Sci. (1998) 31 ;95(7):3978- 83), Chowers (Br J Ophthalmol (2001) 85(8):991-5), Rasmussen (Hum Gene Ther. (2001) 12(16):2029-32, clinical trial for AMD) and are reviewed in Dejenka (Bioassays. (2001) 23(7):662-8).

The nucleic acid molecules and vectors of the invention may be designed for direct introduction or for introduction via liposomes, viral vectors (e.g. adenoviral, retroviral, lentiviral), electroporation, ballistic (e.g. gene gun) or other delivery systems into the cell. Additionally, a baculoviral system can be used as eukaryotic expression system.

As will be discussed herein below, the nucleic acid molecules may be particularly useful as pharmaceutical compositions. Said pharmaceutical compositions may be employed in gene therapy approaches. In this context, it is envisaged that the nucleic acid molecules and/or vectors of the present invention may be employed to modulate, alter and/or modify the cellular expression and/or intracellular concentration of (poly)peptide(s)/fusionprotein of the invention or of (a) fragment thereof. Said modulation, alteration and/or modification may lead to up- or downregulation of the described (poly)peptide(s) and/or the gene product(s). Furthermore, said therapeutic approache(s) may lead to an alteration and/or modulation of the availability of active (poly)peptide/protein/gene product(s). In this context, the term "active" refers to the ability to perform its (normal) cellular function in an organism.

Advantageously, the above-described vectors of the invention comprises a selectable and/or scorable marker. Selectable marker genes useful for the selection of transformed cells and, e.g., plant tissue and plants are well known to those skilled in the art and comprise, for example, antimetabolite resistance as the basis of selection for dhfr, which confers resistance to methotrexate (Reiss, Plant Physiol. (Life Sci. Adv.) 13 (1994), 143-149); npt, which confers resistance to the aminoglycosides neomycin, kanamycin and paromycin (Herrera-Estrella, EMBO J. 2 (1983), 987-995) and hygro, which confers resistance to hygromycin (Marsh, Gene 32 (1984), 481-485). Additional selectable genes have been described, namely trpB, which allows cells to utilize indole in place of tryptophan; hisD, which allows cells to utilize histinol in place of histidine (Hartman, Proc. Natl. Acad. Sci. USA 85 (1988), 8047); mannose-6-phosphate isomerase which allows cells to utilize mannose (WO 94/20627) and ODC (ornithine decarboxylase) which confers resistance to the ornithine decarboxylase inhibitor, 2-(difluoromethyl)-DL-ornithine, DFMO (McConlogue, 1987, In: Current Communications in Molecular Biology, Cold Spring Harbor Laboratory ed.) or deaminase from Aspergillus terreus which confers resistance to Blasticidin S (Tamura, Biosci. Biotechnol. Biochem. 59 (1995), 2336-2338).

Useful scorable marker are also known to those skilled in the art and are commercially available. Advantageously, said marker is a gene encoding luciferase (Giacomin, PI. Sci. 116 (1996), 59-72; Scikantha, J. Bact. 178 (1996), 121), green fluorescent protein (Gerdes, FEBS Lett. 389 (1996), 44-47) or ^β-glucuronidase (Jefferson, EMBO J. 6 (1987), 3901-3907). This embodiment is particularly useful for simple and rapid screening of cells, tissues and organisms containing a vector of the invention.

The present invention furthermore relates to host cells produced by introducing the aforementioned vector or the aforementioned nucleic acid molecule into the host cell. Preferably presence of said vector or nucleic acid molecule in the cell mediates the expression of a gene encoding the nucleic acid molecule of the invention or comprising a vector as described above or a polynucleotide according to the invention wherein the polynucleotides and/or nucleic acid molecule is foreign to the host cell.

By "foreign" it is meant that the polynucleotide or nucleic acid molecule is either heterologous with respect to the host cell, this means derived from a cell or organism with a different genomic background, or is homologous with respect to the host cell but located in a different genomic environment than the naturally occurring counterpart of said nucleic acid molecule. This means that, if the nucleic acid molecule is homologous with respect to the host cell, it is not located in its natural location in the genome of said host cell, in particular it is surrounded by different genes. In this case the polynucleotide may be either under the control of its own promoter or under the control of a heterologous promoter. The vector or nucleic acid molecule according to the invention which is present in the host cell may either be integrated into the genome of the host cell or it may be maintained in some form extrachromosomally. In this respect, it is also to be understood that the nucleic acid molecule of the invention can be used to restore or create a mutant gene via homologous recombination. The host cell can be any prokaryotic or eukaryotic cell, such as a bacterial, insect, fungal, plant or animal cell.

The term "prokaryotic" is meant to include all bacteria which can be transformed or transfected with a DNA or RNA molecule for the expression of a protein of the invention. Prokaryotic hosts may include gram negative as well as gram positive bacteria such as, for example, E. coli, S. typhimurium, Serratia marcescens and Bacillus subtilis. The term "eukaryotic" is meant to include yeast, higher plant, insect and preferably mammalian cells. Depending upon the host employed in a recombinant production procedure, the protein encoded by the polynucleotide of the present invention may be glycosylated or may be non-glycosylated. A polynucleotide of the invention can be used to transform or transfect the host using any of the techniques commonly known to those of ordinary skill in the art. Furthermore, methods for preparing fused, operably linked genes and expressing them in, e.g., mammalian cells and bacteria are well-known in the art (Sambrook, loc. cit.).

In a preferred embodiment the host cell is a human cell or derived from a human cell line.

Moreover, the present invention relates to a method for the production of a (poly)peptide or an immunologically active or functional fragment thereof comprising culturing the aforementioned host cell under conditions allowing the expression of the (poly)peptide and recovering the produced (poly)peptide from the culture.

The term "immunologically active" as used herein refers to proteins or fragments thereof which are characterized by their capability to induce an immunological response in an immunized organism. Said response may be induced by the protein or fragment thereof either alone or in combination with a hapten, an adjuvant or other compounds known in the art to induce or elicit immune responses to a protein or fragment thereof.

The term "functional fragment" as used herein refers to a fragment of said protein having the same function as said protein. In particular, a "functional fragment" of said protein can be characterized, e.g. by catalyzing the same enzymatic activities or inducing immune reactions against the same epitope(s) as the full protein itself. Thus a "functional fragment" of said protein may be a fragment comprising at least one functional prosthetic group and/or at least one specific, preferably non-linear, epitope of the full protein. Isolation and purification of the recombinantly produced proteins may be carried out by conventional means including preparative chromatography and affinity and immunological separations involving affinity chromatography with monoclonal or polyclonal antibodies specifically interacting with said proteins. Preferably, said antibodies are antibodies of the invention as described herein below. As used herein, the term ..isolated protein" includes proteins substantially free of other proteins, nucleic acids, lipids, carbohydrates or other materials with which it is naturally associated. Such proteins however not only comprise recombinantly produced proteins but include isolated naturally occurring proteins, synthetically produced proteins, or proteins produced by a combination of these methods. Means for preparing such proteins are well understood in the art. The proteins of the invention are preferably in a substantially purified form. A recombinantly produced version of said proteins, including secreted proteins, can be substantially purified by the one-step method described in Smith and Johnson, 1988.

In a further preferred embodiment the invention relates to a (poly)peptides or an immunologically active or functional fragment thereof encoded by an above described nucleic acid molecules of the invention or obtainable by the above described method.

Advantageously, in one embodiment said (poly)peptide has the same function as above but carries at least one conservative amino acid substitution.

Preferably said protein or fragment thereof is glycosylated, phosphorylated, amidated and/or myristylated.

Furthermore, the present invention relates to an antibody or fragment or derivative thereof or an aptamer specifically recognizing the aforementioned (poly)peptide or a fragment or epitope thereof, wherein said fragment or epitope has the same structural conformation as the corresponding portion of the native . Said antibody may be a monoclonal or a polyclonal antibody.

Said antibody, which is monoclonal antibody, polyclonal antibody, single chain antibody, or fragment thereof that specifically binds said peptide or polypeptide also including bispecific antibody, synthetic antibody, antibody fragment, such as Fab, a F(ab₂)', Fv or scFv fragments etc., or a chemically modified derivative of any of these (all comprised by the term "antibody"). Monoclonal antibodies can be prepared, for example, by the techniques as originally described in Kohler and Milstein, Nature 256 (1975), 495, and Galfre, Meth. Enzymol. 73 (1981), 3, which comprise the fusion of mouse myeloma cells to spleen cells derived from immunized mammals with modifications developed by the art. Furthermore, antibodies or fragments thereof to the aforementioned peptides can be obtained by using methods which are described, e.g., in Harlow and Lane "Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988. When derivatives of said antibodies are obtained by the phage display technique, surface plasmon resonance as employed in the BIAcore system can be used to increase the efficiency of phage antibodies which bind to an epitope of the peptide or polypeptide of the invention (Schier, Human Antibodies Hybridomas 7 (1996), 97- 105; Malmborg, J. Immunol. Methods 183 (1995), 7-13). The production of chimeric antibodies is described, for example, in WO89/09622. A further source of antibodies to be utilized in accordance with the present invention are so-called xenogenic antibodies. The general principle for the production of xenogenic antibodies such as human antibodies in mice is described in, e.g., WO 91/10741 , WO 94/02602, WO 96/34096 and WO 96/33735. Antibodies to be employed in accordance with the invention or their corresponding immunoglobulin chain(s) can be further modified using conventional techniques known in the art, for example, by using amino acid deletion(s), insertion(s), substitution(s), addition(s), and/or recombination(s) and/or any other modification(s) known in the art either alone or in combination. Methods for introducing such modifications in the DNA sequence underlying the amino acid sequence of an immunoglobulin chain are well known to the person skilled in the art; see, e.g., Sambrook, Molecular Cloning A Laboratory Manual, Cold Spring Harbor Laboratory (1989) N.Y. The term "monoclonal" or "polyclonal antibody" (see Harlow and Lane, "Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, USA, 1988) also relates to derivatives of said antibodies which retain or essentially retain their binding specificity. Whereas particularly preferred embodiments of said derivatives are specified further herein below, other preferred derivatives of such antibodies are chimeric antibodies comprising, for example, a mouse or rat variable region and a human constant region. The term "scFv fragment" (single-chain Fv fragment) is well understood in the art and preferred due to its small size and the possibility to recombinantly produce such fragments.

The term "specifically binds" in connection with the antibody used in accordance with the present invention means that the antibody etc. does not or essentially does not cross-react with (poly)peptides of similar structures. Cross-reactivity of a panel of antibodies etc. under investigation may be tested, for example, by assessing binding of said panel of antibodies etc. under conventional conditions (see, e.g., Harlow and Lane, loc. cit.) to the (poly)peptide of interest as well as to a number of more or less (structurally and/or functionally) closely related (poly)peptides. Only those antibodies that bind to the (poly)peptide of interest but do not or do not essentially bind to any of the other (poly)peptides which are preferably expressed by the same tissue as the (poly)peptide of interest, e.g. by the retina, the retinal pigment epithelium (RPE) or by the chorioidea, are considered specific for the (poly)peptide of interest and selected for further studies in accordance with the method of the invention.

A preferred embodiment of the invention relates to an antibody which is a monoclonal antibody.

In a further alternative embodiment the present invention relates to a transgenic non-human mammal whose somatic and germ cells comprise at least one nucleic acid sequence encoding a functional aforementioned (poly)peptide wherein said nucleic acid sequence optionally has been modified, said modification being sufficient to increase the amount or activity of said functional (poly) peptide having the same or essentially the same function as the (poly)peptide having the amino acid sequence depicted in figure 4.

A method for the production of a transgenic non-human animal, for example transgenic mouse, comprises introduction of the aforementioned polynucleotide or targeting vector into a germ cell, an embryonic cell, stem cell or an egg or a cell derived therefrom. The non-human animal can be used in accordance with the invention in a method for identification of compounds, described herein below. Production of transgenic embryos and screening of those can be performed, e.g., as described by A. L. Joyner Ed., Gene Targeting, A Practical Approach (1993), Oxford University Press. The DNA of the embryonal membranes of embryos can be analyzed using, e.g., Southern blots with an appropriate probe; see supra. A general method for making transgenic non-human animals is described in the art, see for example WO 94/24274. For making transgenic non-human organisms (which include homologously targeted non-human animals), embryonal stem cells (ES cells) are preferred. Murine ES cells, such as AB-1 line grown on mitotically inactive SNL76/7 cell feeder layers (McMahon and Bradley, Cell 62:1073-1085 (1990)) essentially as described (Robertson, E. J. (1987) in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach. E. J. Robertson, ed. (Oxford: IRL Press), p. 71-112) may be used for homologous gene targeting. Other suitable ES lines include, but are not limited to, the E14 line (Hooper et al., Nature 326:292-295 (1987)), the D3 line (Doetschman et al., J. Embryol. Exp. Morph. 87:27-45 (1985)), the CCE line (Robertson et al., Nature 323:445-448 (1986)), the AK-7 line (Zhuang et al., Cell 77:875-884 (1994)). The success of generating a mouse line from ES cells bearing a specific targeted mutation depends on the pluripotence of the ES cells (i. e., their ability, once injected into a host developing embryo, such as a blastocyst or morula, to participate in embryogenesis and contribute to the germ cells of the resulting animal). The blastocysts containing the injected ES cells are allowed to develop in the uteri of pseudopregnant non-human females and are born, e.g. as chimeric mice. The resultant transgenic mice are chimeric for cells having either the recombinase or reporter loci and are backcrossed and screened for the presence of the correctly targeted transgene (s) by PCR or Southern blot analysis on tail biopsy DNA of offspring so as to identify transgenic mice heterozygous for either the recombinase or reporter locus/loci.

The transgenic non-human animals may, for example, be transgenic mice, rats, hamsters, dogs, monkeys, rabbits, pigs, or cows. Preferably, said transgenic non- human animal is a mouse.

In a further preferred embodiment of the transgenic non-human mammal of the invention the modification is activation or overexpression of said nucleic acid sequence or leads to the enhancement of the synthesis of the corresponding protein.

This embodiment allows for example the study of the interaction of various mutant forms of the aforementioned (poly)peptides on the onset of the clinical symptoms of retinal diseases which concern the expression of certain isoforms or mutant forms of proteins encoded by the aforementioned nucleic acid molecules. All the applications that have been herein before discussed with regard to a transgenic animal also apply to animals carrying two, three or more transgenes for example encoding different aforementioned nucleic acid molecules. It might be also desirable to inactivate or, more preferably, to enhance protein expression or function at a certain stage of development and/or life of the transgenic animal. This can be achieved by using, for example, tissue specific, developmental and/or cell regulated and/or inducible promoters which drive the expression of the transgen. A suitable inducible system is for example tetracycline-regulated gene expression as described, e.g., by Gossen and Bujard (Proc. Natl. Acad. Sci. 89 USA (1992), 5547-5551) and Gossen et al. (Trends Biotech. 12 (1994), 58-62) or the interferon- α/β induce expression of genes under control of the Mx-promoter (Dulat et al., Transplant Proc (2001);33 (1-2):262-3). Similar, the expression of the mutant protein(s) may be controlled by such regulatory elements. As mentioned, the invention also relates to a transgenic non-human animal, preferably mammal and cells of such animals which cells contain (preferably stably integrated into their genome) at least one of the aforementioned nucleic acid molecule(s) or part thereof, wherein the transcription and/or expression of the nucleic acid molecule or part thereof leads to induction of the synthesis of (a) corresponding protein(s). Techniques how to achieve this are well known to the person skilled in the art.

However, it is also possible to use nucleic acid molecules which display a high degree of homology to endogenously occurring nucleic acid molecules encoding such a protein. In this case the homology is preferably higher than 65%, preferably at least 80%, especially at least 90%, most preferred at least 99%. In cases where aforementioned gene is enhanced, optionally in combination with a modification of the function and/or expression of one or more further gene products, interrelationships of gene products in the onset or progression of retinal diseases may be assessed. In this regard, it is also of interest to cross transgenic non-human animals having different transgenes for assessing further interrelationships of gene products in the onset or progression of said disease. Consequently, the offspring of such crosses is also comprised by the scope of the present invention.

Moreover, according to a further preferred embodiment the present invention relates to a transgenic non-human mammal as described herein above, wherein the modification is activation or enhancement of said nucleic acid sequence or leads to the increment of the synthesis of the corresponding protein.

Production of transgenic embryos and screening of those can be performed, e.g., as described by Joyner (1993). The DNA of the embryonal membranes of embryos can be analyzed using, e.g., Southern blots with an appropriate probe.

According to an alternative embodiment the present invention relates to a transgenic non-human mammal whose somatic and germ cells lack a nucleic acid sequence encoding a functional form of the aforementioned (poly)peptide or show a deficiency in the activity or expression of said (poly)peptide.

Methods for the production of animals lacking genes encoding functional peptides, in particular, methods for the production of knock-out animals are well known in the art.

The above mentioned "underexpression" of the nucleic acid molecule of the invention comprises, inter alia, full deletion of both alleles, or the deletion of one allele. Furthermore, said term comprises the generation of a mutation which leads to the expression of a less functional protein/(poly)peptide or a diminished function of the encoded (poly)peptides in an animal.

The phenotype of said transgenic non-human mammal compared to wild type animals may result from:

(a) disruption of at least one endogenous gene of the invention; (b) expression of at least on antisense RNA and/or ribozyme against a transcript comprising a nucleic acid molecule(s) of the invention;

(c) expression of a non-translatable mRNA of the nucleic acid molecule(s) of the invention; (d) expression of an antibody of the invention which inhibits the function of at least one (poly)peptide encoded by the nucleic acid molecule(s) of the invention; or (e) incorporation of a non-functional copy at least one gene of the invention.

According to a preferred embodiment the transgenic non-human mammal of the invention is an animal, wherein said nucleic acid sequence was introduced into the non-human mammal or an ancestor thereof, at an embryonic stage.

The present invention also relates in an alternative embodiment to a method for the diagnosis of a retinal disease or a predisposition for a retinal disease of a subject comprising the steps of:

(a) contacting a sample isolated from said subject or from cells isolated from said subject or in a subject, suspected to contain at least one isoform or mutated form of the (poly)peptide of the invention or of a (poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 1 1 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridizing with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(iv) being encoded by a nucleic acid molecule derived from the

(poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. with a receptor specific for said (poly)peptide ; and

(b) detecting or quantitating the amount of said protein in said sample; wherein the presence or amount of said isoform or mutated form is indicative of a retinal disease.

The term "retinal disease" means, in accordance with the present invention, any disease that affects the normal function of the retina. This definition includes hereditary as well as acquired diseases such as diseases induced by a pathogen. This definition includes hereditary diseases like Best vitelliform macular dystrophy or X-linked juvenile retinoschisis, as well as acquired diseases such as diseases induced by a pathogen, e.g. Herpesretinitis, an acute form of a retinal necrosis caused by Herpes-simplex virus or Chorioretinitis, which is often a side effect of toxoplasmosis. In accordance with the present invention, it has surprisingly been found that a variety of further nucleic acid sequences and corresponding (poly)peptides are involved in the occurrence of retinal diseases. Whereas some of the functions of the (poly)peptides had been speculated about in the art, there was no indication that these molecules could have any impact on the etiology of the diseases of the retina (retinal diseases). Thus, the protein depicted in figure 6 has been characterized as a serine/threonine-preotein kinase 35, the protein depicted in figure 8 has been characterized as a serine/threonine-preotein kinase MAK . This embodiment of the invention makes use of the option to the level of the (poly)peptide translated from the mRNA in a certain tissue or population of cells. Whereas it is not excluded that the level of mRNA strictly correlates with the level of (poly)peptide translated from the mRNA, this may not always be the case. Accordingly, it may be assessed whether the mRNA level, which can be detected according to a further embodiment of the present invention described herein below, or the protein level, if different, is more appropriate to establish if a subject is prone to develop a retinal disease. Factors that contribute to differences in the expression levels of mRNA and protein are well-known in the art and include differential mRNA-export to the protein-synthesis machinery as well as differences in the translation efficacy of different mRNA species. Other considerations influencing the choice of the detection level (in RNA or protein) include the availability of an appropriate screening tool, instrumentation of the lab, experience of the lab personnel and others.

Increased or decreased expression of the product of a gene in affected individuals as compared to unaffected individuals can be assessed using classical immunohistological methods (Jalkanen et al., 1985; Jalkanen et al., 1987; Sobol et al. (1982); Sobol et al., (1985). Other antibody based methods useful for detecting protein gene expression include immunoassays, such as the enzyme-linked immunosorbent assay (ELISA) and the radioimmunoassay (RIA). Suitable antibody assay labels are known in the art and include enzyme labels, such as, glucose oxidase, and radioisotopes, such as iodine (¹²⁵l, ¹²¹l), carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium (¹¹²ln), and technetium (⁹⁹Tc), and fluorescent labels, such as fluorescein and rhodamine, and biotin. Said method for the diagnosis of a retinal disease or a predisposition for a retinal disease of a subject comprises also methods which are carried out in the subject itself. For example a detectably labeled substance may be used as contrast agent. Said substances may be, e.g. an aforementioned antibody may be injected into the bloodstream or the eye. The step of detection or quantification may then comprise an optical analysis of the eye or the background of the eye.

For the diagnosis of a retinal disease or a predisposition for a retinal disease the amount of a wt-isoform present in said sample is indicative of the disease. In case of detection of a mutated form the presence of said mutated form of the protein of the invention may already be sufficient for the diagnosis of a retinal disease or a predisposition for a retinal disease.

The term "receptor" is defined in accordance with the present invention as a substance that specifically binds to the protein measured by the method of the invention. Said substances comprise a characteristic binding domain by which they interact with the target protein. Examples for receptors according to the invention are, e.g. peptides, antibodies and fragments or derivatives thereof, aptamers, or small molecules. The term "specifically binds" is used in this context as defined herein above in connection with antibodies.

In a preferred embodiment of the method of the invention, the presence or the amount of said isoforms or mutated forms is quantitated using an aptamer or an antibody or an antigen-binding portion of said aptamer or antibody that specifically binds to said protein or its isoforms or mutated forms.

The antibody used in accordance with the invention may be a monoclonal or a polyclonal antibody (see Harlow and Lane, "Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, USA, 1988) or a derivative of said antibody which retains or essentially retains its binding specificity. Said antibody may correspond to an antibody described herein above. Whereas particularly preferred embodiments of said derivatives are specified further herein below, other preferred derivatives of such antibodies are chimeric antibodies comprising, for example, a mouse or rat vaπable region and a human constant region.

The term "specifically binds" in connection with the antibody used in accordance with the present invention has been defined herein above. In a particularly preferred embodiment of the method of the invention, said antibody or antibody binding portion is or is derived from a human antibody or a humanized antibody. The term "humanized antibody" means, in accordance with the present invention, an antibody of non-human origin, where at least one complementarity determining region (CDR) in the variable regions such as the CDR3 and preferably all 6 CDRs have been replaced by CDRs of an antibody of human origin having a desired specificity. Optionally, the non-human constant region(s) of the antibody has/have been replaced by (a) constant region(s) of a human antibody. Methods for the production of humanized antibodies are described in, e.g., EP-A1 0 239 400 and WO90/07861.

In an also particularly preferred embodiment of the method of the invention the antibody or fragment or derivative thereof is the antibody particularly described herein above.

In an additionally preferred embodiment of the method of the invention, said fragment of said antibody is a Fab-, a F(ab')₂- and said derivative is an scFv- fragment.

The specifically binding antibody etc. may be detected by using, for example, a labeled secondary antibody specifically recognizing the constant region of the first antibody. However, in a further particularly preferred embodiment of the method of the invention, the aptamer or the antibody or derivative of said aptamer or antibody or derivative thereof itself is detectably labeled.

Detectable labels include a variety of established labels such as radioactive (^12δl, for example) or fluorescent labels (see, e.g. Harlow and Lane, loc. cit.). Binding may be detected after removing unspecific labels by appropriate washing conditions (see, e.g. Harlow and Lane, loc. cit.).

A variety of techniques are available for labeling biomolecules, are well known to the person skilled in the art and are considered to be within the scope of the present invention. Such techniques are, e.g., described in Tijssen (1985), Davis LG et al. (1990), Mayer et al., (1987), or in the series "Methods in Enzymology" (Academic Press, Inc.). There are many different labels and methods of labeling known to those of ordinary skill in the art. Commonly used labels comprise, inter alia, fluorochromes (like fluorescein, rhodamine, Texas Red, etc.), enzymes (like horse radish peroxidase, beta-galactosidase, alkaline phosphatase), radioactive isotopes (like ³²P or ^{1 5}l), biotin, digoxygenin, colloidal metals, chemo- or bioluminescent compounds (like dioxetanes, luminol or acridiniums). Labeling procedures, like covalent coupling of enzymes or biotinyl groups, iodinations, phosphorylations, biotinylations, random priming, nick-translations, tailing (using terminal transferases) are well known in the art. Detection methods comprise, but are not limited to, autoradiography, fluorescence microscopy, direct and indirect enzymatic reactions, etc.

According to a preferred embodiment of the method of the invention said (poly)peptide is quantitated in an in situ test. An example for such "in situ test" has been described herein above. Methods for the determination of the amount of a particular protein in a specified tissue are known to a person skilled in the art.

In yet another preferred embodiment, the method of the invention further comprises the step of normalizing the amount of in said sample against a corresponding (poly)peptide detected in a sample from a healthy subject or cells derived from a healthy subject. As known to a person skilled in the art said normalization may be proceeded as described for the normalization of expression data for the preparation of expression profiles relative to so called "housekeeping-genes" (see, e.g. Levin, "Genes V", Oxford University Press 1994, page 622 to 623) and described also herein below. In accordance to said proceeding an expression profile of (poly)peptides in a sample is normalized relative to the amount of the gene product of an "housekeeping-gene". The present invention also relates in an alternative embodiment to a method of diagnosing a retinal disease or a predisposition for a retinal disease of a subject, comprising the step of analyzing at least one nucleic acid molecule or quantitating the amount of at least one RNA in a sample of said subject, wherein (a) said at least one nucleic acid sequence or RNA encodes an amino acid sequence consisting of:

(aa) an amino acid sequence as depicted in any of figures 2, 4, 6, 8, 10, 12 or 14;

(ab) an amino acid sequence that is at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence of (aa);

(ac) the amino acid sequence of (aa) with at least one conservative amino acid substitution;

(ad) an amino acid sequence that is an isoform of the amino acid sequence of any of (aa) to (ac); and

(ae) an amino acid that is encoded by a DNA molecule the complementary strand of which hybridizes in 4xSSC, 0.1 % SDS at 65°C to the DNA molecule encoding the amino acid sequence of (aa), (ac) or (ad);

(b) said at least one RNA is transcribed from the DNA sequence as depicted in any of figures 1 , 3, 5, 7, 9, 1 1 or 13 or a degenerate variant thereof; and or

(c) said at least one nucleic acid molecule has the sequence depicted in any one of figures 1 , 3, 5, 7, 9, 11 or 1 1 or a sequence hybridizing under stringent conditions to the complementary strand thereof.

The term "analyzing of at least one nucleic acid sequence" is intended to comprise the analysis of nucleic acid sequence of the aforementioned genes in samples of tissues or cells isolated from a subject and to compare said sequence with the sequence of a healthy subject. The term "healthy subject" in connection with the present invention means a subject without any indication for retinal disease. This comprises in accordance with the invention that there is no indication for a predisposition for said diseases of said subject, neither on protein or on gene level. Said analysis comprise the analysis of regulatory structures of the gene, e.g. promoter structures. The term "quantitating the amount of at least one RNA" is intended to mean the determination of the amount of mRNA in a sample as compared to a standard value such as an internal standard. The (internal) standard would advantageously be the amount of a corresponding RNA produced by a tissue or cell isolated from a healthy subject not affected by a disease. Said (internal) standard would also include a mean value obtained from a variety of corresponding tissues or cells not affected by a disease.

Optionally, a standard would take into account the genetic background of the subject under investigation. Thus, quantitation of said subject's RNA is effected in comparison to the amount of RNA of one or a variety of samples of the same or a similar genetic background. A variable number of "non-failing" humans (humans that do not show an indication for any retinal disease) are compared with a variable number of patients that suffer a distinct retinal disease like macular degeneration. The determination can be effected by any known technology of analyzing the amount of RNA produced in a sample such as a tissue sample. Techniques based on hybridization like Northern-Blot, dot-blot, subtractive hybridization, DNA-Chip analysis or techniques based on reverse transcription coupled to the polymerase chain reaction (RT-PCR) like differential display, RNase protection assays, suppression subtractive hybridization (SSH), fluorescence differential display (FDD), serial analysis of gene expression (SAGE) or representational difference analysis (see e.g. Kozian, D.H., Kirschbaum, B.J.; Comparative gene-expression analysis. (1999) 17:73-77). In particular, said techniques may be in situ methods, e.g. in situ hybridization, in vitro amplification methods (PCR RT-PCR, LCR, QRNA replicase or RNA-transcription/amplification (TAS, 3SR), reverse dot blot disclosed in EP-B1 0 237 362)), immunoassays, Western blot and other detection assays that are known to those skilled in the art. Generally, it is preferred that the assay is performed as a high throughput assay. This holds also true for the further methods described herein and in accordance with this invention. Samples of RNA may be prepared e.g. according to the manufactures' instructions of different kits for isolation of RNA (e.g. RNeasy of QIAGEN).

The term "isoform" has been defined herein above.

The term "DNA molecule the complementary strand of which hybridizes in 4xSSC, 0.1% SDS at 65°C to the DNA molecule encoding the amino acid sequence of (aa), (ac) or (ad)" means that the two DNA molecules hybridize under these experimental conditions to each other. This term does not exclude that the two DNA sequences hybridize at higher stringency conditions such as 2xSSC, 0.1% SDS at 65°C nor does it exclude that lower stringency conditions such as 6xSSC, 0.1% SDS at 60°C allow a hybridization of the two DNA sequences. Stringent conditions for hybridization are well known by a person skilled in the art and described in more detail herein above. The invention is based upon the unexpected result that expression of the genes described herein above coding for the protein sequences referred to above are deregulated when one compares of one or more samples isolated from subjects showing a retinal disease to one or more samples isolated from healthy subjects and lead to an upregulation of the described (poly)peptides and isoforms or mutant forms of said (poly)peptides measured by their respective mRNAs or cDNAs. Significant changes in gene expression levels or pattern of the gene expression of certain isoforms or mutant forms suggest a causative role in retinal diseases. It is well accepted in the art that downregulation of gene expression of a upregulated target gene by means of a gene therapeutic intervention, compensatory molecules or specific inhibitors, for example of transcription or translation are potentially very promising therapeutic tools to treat a retinal disease that are caused or promoted by the upregulation of such gene. Respectively, upregulation of gene expression of a downregulated or non-expressed target gene corresponding means are accepted in the art as therapeutic intervention. By performing the method of the invention which may be in vivo, in vitro or in silico, the diagnosis of a retinal disease established by a different methodology may be corroborated. Alternatively, it may be assessed whether a subject that is preferably throughout this specification a human displaying no sign of being affected by a retinal disease is at risk of developing such a disease. This is possible in cases where the overexpression of the gene defined herein above is causative of the disease or is a member of a protein cascade wherein another gene/protein than the one identified herein above is causative for said disease. In this regard, the term "causative" is not limited to mean that the aberrant expression of one gene as identified above or which is a member of said protein cascade is the sole cause for the onset of the disease. Whereas this option is also within the scope of the invention, expression the invention also encompasses embodiments wherein said aberrant is one of a variety of causative events that lead to the onset of the disease.

There is causal correlation between altered cellular function of retinal cells, cells of the retinal pigment epithelium (RPE) and cells in the Chorioidea and its protein composition. The latter is regulated by three main mechanisms: a. Gene expression b. Alternative splicing c. Posttranslational modification In a variation of the method of the invention quantitation of the above recited RNA is used to monitor the progress of a disease (said variation also applies to the method described herein below). This variation may be employed for assessing the efficacy of a medicament or to determine a time point when administration of a drug is no longer necessary or when the dose of a drug may be reduced and/or when the time interval between administrations of the medicament may be increased. This variation of the method of the invention may successfully be employed in cases where an aberrant expression of any of the aforementioned genes/genes as members of protein cascades is causative of the disease. It is also useful in cases where the aberrant expression of the gene/genes is the direct or indirect result of said disease.

In a preferred embodiment of the method of the invention the amount of the said RNA is quantitated using a nucleic acid probe which

(a) the nucleic acid molecule having the sequence as depicted in any of figures 1 , 3, 5, 7, 9, 11 or 13 or a degenerate variant thereof;

(b) a nucleic acid molecule having a sequence that encodes the amino acid sequence as depicted in any of figures 2, 4, 6, 8, 10, 12 or 14, whereby optionally said amino acid sequence has at least one conservative amino acid substitution; (c) a nucleic acid sequence that hybridizes under stringent conditions to the complementary strand of the nucleic acid molecule encoding the amino acid sequence of (a) or (b);

(d) a fragment of at least 15 nucleotides in length and being part of the sequence of any of (a) to (c); and

(e) a nucleic acid probe comprising a sequence that specifically hybridizes under physiological conditions to the nucleotide sequence of:

(i) the cDNA derived from the RNA transcribed from the DNA sequence as depicted in any of figures 1 , 3, 5, 7, 9, 1 1 or 13; (ii) a DNA sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the DNA sequence of (i); (iii) a nucleic acid sequence that encodes the amino acid sequence as depicted in any of figures 2, 4, 6, 8, 10, 12 or 14 with at least one conservative amino acid substitution;

(iv) a nucleic acid sequence that encodes an amino acid sequence that is at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence of (iii); (v) a nucleic acid sequence that encodes the amino acid sequence of (iii) with at least one conservative amino acid substitution;

(vi) a nucleic acid sequence that hybridizes in 2xSSC, 0.1 % SDS at 65°C to the DNA molecule encoding the amino acid sequence of (iii), (iv) or (v); and (vii) a fragment of at least 15 nucleotides in length and being part of the sequence of (i) to (vi).

In a preferred embodiment of the method of the invention, said nucleic acid or RNA is obtained from retinal tissue.

In another preferred embodiment, the method of the invention further comprises the step of normalizing the amount of RNA against a corresponding RNA from a healthy subject or cells derived from a healthy subject. The term "normalizing the amount of RNA against a corresponding RNA from a healthy subject or cells derived from a healthy subject" means, in accordance with the present invention, that levels of mRNA from a comparative number of cells specific for the tissue layer of the background of the eye of said subject under investigation and from such cells of an individual not affected by a retinal disease are compared. Alternatively, cells from the subject under investigation may be compared in terms of the indicated mRNA levels with cells derived from a healthy individual which are kept in cell culture and optionally form a cell line. Optionally, different sources of cells such as from different individuals and/or different cell lines may be used for the generation of the standard against which the mRNA level of the subject under investigation is compared. Using the Affymetrix Chip technology, there is also the possibility to use external standards (that are given separately to the hybridization cocktail) in order to normalize the values of different oligonucleotide-chips.

Additionally, the invention relates to a method for identifying a compound that modulates the translation level of a (poly)peptide selected from the group consisting of the (poly)peptide of the invention or a (poly)peptide being the preferably mature form of a (poly)peptide : (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 1 1 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridizing with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said

(poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. said method comprising the steps of:

(a) contacting a DNA encoding said (poly)peptide under conditions that permit the translation of said (poly)peptide with a test compound; and

(b) assessing the level of said (poly)peptide wherein a modulated level of the (poly)peptide relative to the level of translation obtained in the absence of the test compound is indicative of the modulating activity of said compound at the translation level. Preferred compounds are nucleic acids, preferably coding for a peptide, (poly)peptide, antisense RNA or a ribozyme or nucleic acids used for example by RNAi-technology that act independently of their transcription respective their translation as for example an antisense RNA or ribozyme; natural or synthetic peptides, preferably with a relative molecular mass of about 1 ,000, especially of about 500, peptide analogs, (poly)peptides or compositions of (poly)peptides, proteins, protein complexes, fusion proteins, antibodies, especially murine, human or humanized antibodies, single chain antibodies, Fab fragments or any other antigen binding portion or derivative of an antibody as defined above, including modifications of such molecules as for example glycosylation, acetylation, phosphorylation, farnesylation, hydroxylation, methylation or esterification, hormones, or other organic or inorganic molecules or compositions. The term "under conditions that would permit the translation of said (poly)peptide" denotes any condition that allow the in vitro or in vivo translation of the (poly)peptide of interest. As regards in vitro conditions, translation may be effected in a cell-free system, as described, for example in Stoss, Schwaiger, Cooper and Stamm (1999). J. Biol. Chem. 274: 10951-10962, using the TNT-coupled reticulocyte lysate system (Promega). With respect to in vivo conditions, physiological conditions such as conditions naturally occurring inside a cell are preferred.

Based on the finding that expression of genes encoding the above recited (poly)peptides is aberrant, the method of the invention allows the convenient identification or isolation of compounds that counteract such aberrant expression such that normal expression levels are restored or essentially restored. In the case that the method of the invention is carried out in vitro, for example, in a cell-free system, then introduction into a cell would not be necessary in order to obtain a meaningful results. Rather, the test compound would be admixed to the in vitro expression system and the effect of said admixture observed. The effect of the contact of the DNA of interest with the test compound on the protein level may be assessed by any technology that measures changes in the quantitative protein level. Such technologies include Western blots, ELISAs, RIAs and other techniques referred to herein above.

The change in protein level (modulations), if any, as a result of the contact of said DNA and said test compound is compared against a standard. This standard is measured applying the same test system but omits the step of contacting the testcompound with the DNA. The standard may consist of the expression level of the (poly)peptide after no compound has been added. Alternatively, the DNA may be contacted with a compound that has previously been demonstrated to have an influence on the expression level. Compounds tested positive for being capable of modulating the amount of (poly)peptide produced are prime candidates for the direct use as a medicament or as lead compounds for the development of a medicament. Naturally, the toxicity of the compound identified and other well-known factors crucial for the applicability of the compound as a medicament will have to be tested. Methods for developing a suitable active ingredient of a pharmaceutical composition on the basis of the compound identified as a lead compound are described elsewhere in this specification.

Additionally, the invention relates to a method for identifying a compound that specifically binds to or interacts with a (poly)peptide of the invention or a (poly)peptide being the preferably mature form of a (poly)peptide : (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridizing with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said

(poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. said method comprising the steps of:

(a) providing said (poly)peptide;

(b) contacting one or a plurality of compounds with said (poly)peptide; and

(c) identifying one or a plurality of compounds that is capable of binding to or interacting with said (poly)peptide.

A "test for interaction" of the above described method may be carried out by specific immunological and/or biochemical assays which are well known in the art and which comprise, e.g., homogenous and heterogenous assays as described herein below. Said binding or interaction assays employing read-out systems are well known in the art and comprise, inter alia, two hybrid screenings (as, described,, inter alia, in EP-0 963 376, WO 98/25947, WO 00/02911), GST-pull-down columns, co- precipitation assays from cell extracts as described, inter alia, in Kasus-Jacobi, Oncogene 19 (2000), 2052-2059, "interaction-trap" systems (as described, inter alia, in US 6,004,746) expression cloning (e.g. lamda gtll), phage display (as described, inter alia, in US 5,541 ,109), in vitro binding assays and the like. Further interaction assay methods and corresponding read out systems are, inter alia, described in US 5,525,490, WO 99/51741 , WO 00/17221 , WO 00/14271 , WO 00/05410 or Yeast Four hybrid assays as described in Sandrok & Egly, JBC 276 (2001), 35328-35333.

Said interaction assays also comprise assays for dimerization, oligomerization and/or multimerization, like FRET-assays (fluorescence resonance energy transfer; as described, inter alia, in Ng, Science 283 (1999), 2085-2089 or Ubarretxena- Belandia, Biochem. 38 (1999), 7398-7405), or fluorescence polarization assays. These methods are well known in the art and inter alia described in Fernandez, Curr. Opin. Chem. Biol. 2 (1998), 547-603. Also included are TR-FRETs (in „A homogenius time resolved fluorescence method for drug discovery" in: High throughput screening: the discovery of bioactive substances. Kolb, (1997) J.Devlin. NY, Marcel Dekker 345-360) or commercially available assays, like „Amplified Luminescent Proximity Homogenous Assay", BioSignal Packard. Furthermore, the yeast-2-hybrid (Y2H) system may be employed to elucidate further particular and specific interaction and/or association partners of the (poly)peptides comprised in the complex of the invention or of fragments thereof.

Similarly, interacting molecules/(poly)peptides may be deduced by cell-based techniques well known in the art. These assays comprise, inter alia, the expression of reporter gene constructs or "knock-in" assays, as described, for, e.g., the identification of drugs/small compounds influencing the gene expression. Said "knock-in" assays may comprise "knock-in" in tissue culture cells, as well as in (transgenic) animals. It is, inter alia, envisaged that such "knock-in assays" comprise the expression of nucleic acid molecules or a fragment or a derivative thereof in combination with at least of any of a gene identified by a method of the invention. Examples for successful "knock-ins" are known in the art (see, inter alia, Tanaka, J. Neurobiol. 41 (1999), 524-539 or Monroe, Immunity 11 (1999), 201- 212). Furthermore, biochemical assays may be employed which comprise, but are not limited to, binding of the (poly)peptides of the invention (or (a) fragment(s) thereof) to other molecules/(poly)peptides, peptides or binding of the (poly)peptides of the invention (or (a) fragment(s) thereof) to itself (themselves) (dimerizations, oligomerizations, multimerizations) and assaying said interactions by, inter alia, scintillation proximity assay (SPA) or homogenous time-resolved fluorescence assay (HTRFA). A "testing of interaction" may also comprise the measurement of a complex formation. The measurement of a complex formation is well known in the art and comprises, inter alia, heterogeneous and homogeneous assays. Homogeneous assays comprise assays wherein the binding partners remain in solution and comprise assays, like agglutination assays. Heterogeneous assays comprise assays like, inter alia, immuno assays, for example, ELISAs, RIAs, IRMAs, FIAs, CLIAs or ECLs.

Further methods and assays for identifying interaction and/or binding partners of the proteins/fusionproteins of the invention or for the identification of agents/compounds which are capable of interfering with the binding of the proteins/fusionproteins with this (specific) intracellular binding partners/targets are disclosed herein below. Thereby, it is also envisaged and demonstrated herein, that a (specific) intracellular binding partner is the (poly)peptide of the invention itself and that the interfering molecule might interfere with dimerization, oligomerization and/or multimerization of the inventive molecules or the enzymatic modification of the inventive (poly)peptide or a target substrate of the inventive (poly)peptide. Methods to identify compounds capable of binding also include affinity chromatography with immobilized target protein and subsequent elution of bound proteins (e. g. by acid pH), co-immunoprecipitation and chemical crosslinking with subsequent analysis on SDS-PAGE.

The influence of compounds on these protein-protein interactions can be monitored by techniques like optical spectroscopy (e. g. fluorescence or surface plasmon resonance), calorimetry (isothermal titration microcalorimetry) and NMR. In the case of optical spectroscopy either the intrinsic protein fluorescence may change (in intensity and/or wavelength of emission maximum) upon complex formation with the binding compound or the fluorescence of a covalently attached fluorophore may change upon complex formation. The claimed protein or its identified binding partner may be labelled on e. g. cysteine or lysine residues with a fluorophore (for a collection of fluorophores see catalogues of Molecular Probes or Pierce Chemical Company) which changes its optical properties upon binding. These changes in the intrinsic or extrinsic fluorescence may be applied for use in a HTS assay to identify compounds capable of inhibiting or activating the mentioned protein-protein interaction.

If the protein referred to above exhibits enzymatic activity (e. g. kinase, protease, phosphatase) the activation or inhibition of this activity may be monitored by using labelled, (fluorescently, radioactively or immunologically) derivates of the substrate. This activity assay which is based on labeled substrates can be used for development of a HTS assay to identify compounds acting as activator or inhibitor. Any measuring or detection step of the method(s) of the present invention may be assisted by computer technology. For example, in accordance with the present invention, said detection and/or measuring step can be automated by various means, including image analysis, spectroscopy or flow cytometry. Therefore, the detection/measuring step(s) of the method(s) of the invention can be easily performed according to methods known in the art such as described herein. In particular, the detection/measuring step(s) of the method(s) of the invention can be carried out by employing antibodies directed against the (poly)peptides of the invention. Said antibodies may comprise conformation-dependent antibodies. The use of antibodies is particularly preferred in detection methods like ELISA. In accordance with the above, the identification of binding or interaction is assesed with a readout system.

The term "readout system" in context with the present invention means any substrate that can be monitored, for example due to enzymatically induced changes. Said "readout system" may also comprise the use of specifically labeled (poly)peptides of the invention. These labels comprise, but are not limited to, radioactive labels, biotin, β-Gal, dioxygenin, fluorescence labels, chemi- or bioluminescent labels or protein labels, like GFP and the like.

In a preferred embodiment of the method of the invention said binding results in a modulation of the activity of said (poly)peptide. The term "modulation" defines in accordance with the present invention a variation of a measured value in comparison to a reference value. Said reference value may be, e.g. obtained from a control sample or a normalized sample. The modulation of the value may be an increase/enhancement of the measured value (e.g. an upregulation of an activity or expression of a protein) as well as a decrease/inhibition of the measured value (e.g. an downregulation of an activity or expression of a protein).

Methods to determine the modulation of a activity of an (poly)peptide are known in the art. Said methods are, e.g. kinase-assays or phosphatase-assays. Assays to determine or analyze protein/protein-interaction domains comprise e.g. yeast-two- hybrid systems, in vitro pull-down assays and far-western blots and are described herein above. For this purpose first proteins may be identified which are binding partners of the described proteins. This is especially useful for structural proteins or adaptor proteins in signal transduction pathways.

Moreover, the invention relates to a method for identifying a compound that modulates the level of an mRNA encoding a (poly)peptide is the preferably mature form of a (poly)peptide selected from the group consisting of the (poly)peptide of the invention or a (poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridizing with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, in a cell or a tissue, said method comprising the steps of (i) contacting a DNA giving rise to said mRNA under conditions that would permit transcription of said mRNA with a test compound; and (ii) assessing the level of transcribed mRNA wherein a modulated level of the mRNA relative to the level of transcription obtained in the absence of the test compound is indicative of the modulating activity of said compound at the translation level.

This embodiment of the invention is very similar to the previously discussed one with the exception that here mRNA levels are detected whereas in the previous embodiment protein levels are detected. Methods of assessing RNA levels which may be used in this embodiment have been described herein above. The level of mRNA may be measured e.g. in retinal cells, cells of the retinal pigment epithelium (RPE) and cells of the Chorioidea

An alternative embodiment of the invention relates to a method for identifying a compound that modulates the expression of a (poly)peptide in a cell or a tissue, the (poly)peptide being selected from the group consisting of the (poly)peptide of the invention or of a (poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridizing with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, said method comprising the steps of:

(i) contacting a transgenic non-human mammal according to the inveintion with a test compound, and

(ii) assessing the level of a (poly)peptide wherein a modulated expression of a (poly)peptide relative to the level of expression obtained in the absence of the test compound is indicative of the modulating activity of said compound at the expression level.

In a preferred embodiment of the method of the invention the test compound prevents or ameliorates a retinal disease in said transgenic non-human mammal. In this embodiment, the effect of the test compound may be assessed by observing the disease state of the transgenic animal. Thus, if the animal suffers from a retinal disease prior to the administration of the test compound and the administration of the test compound results in an amelioration of the disease, then it can be concluded that this test compound is a prime candidate for the development of a medicament useful also in humans. In addition the compound could also inhibit disease establishment by treatment in advance.

According to a preferred embodiment of the invention said modulation is an inhibition or decrease of the expression.

In an alternative embodiment said modulation is an induction or enhancement of the expression.

The invention further relates to method for identifying one or a plurality of genes the expression of which is modulated by the inhibition or decrease of the expression or activity of a (poly)peptide selected from the group consisting of the (poly)peptide of the invention or of a (poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. or by the inhibition or decrease of the expression of an mRNA encoding said (poly)peptide, said modulation being indicative of a retinal disease, said method comprising the steps of: (i) contacting a plurality of cells with a compound that inhibits or decreases the expression or activity of said (poly)peptide under conditions that permit the expression of said (poly)peptide in the absence of said compound, and

(ii) . comparing gene expression profiles of said cells in the presence and in the absence of said compound.

Furthermore, the invention relates to a method for identifying one or a plurality of genes the expression of which is modulated by the induction or enhancement of the expression or activity of a (poly)peptide selected from the group consisting of the (poly)peptide of the invention or of a (poly)peptide being the preferably mature form of a (poly) peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 1 1 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said

(poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%o, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said

(poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. or by the induction or enhancement of the expression of a mRNA encoding said (poly)peptide, said modulation being indicative of a retinal disease, said method comprising the steps of: (i) contacting a plurality of with a compound that inhibits or decreases the expression of said (poly)peptide under conditions that permit the expression or activity of said (poly)peptide in the absence of said compound, and

(ii) comparing gene expression profiles of said cells in the presence and in the absence of said compound. Cells used in this methods may be e.g. retinal cells, cells of the retinal pigment epithelium (RPE) or cells in the Chorioidea. The above described analysis of the expression of genes results in so called "gene expression profiles" The term "gene expression profile" shall mean a compilation of all expressed genes of a cell or a tissue. Such profile can be assessed using methods well known in the art, for example isolation of total RNA, isolation of poly(A) RNA from total RNA, suppression subtractive hybridization, differential display, 2-dimention gel electrophoresis, preparation of cDNA libraries or quantitative dot blot analysis. Said method of the invention is particularly suitable for identifying further genes the expression level of which is directly affected by the aberrant expression of any of the aforementioned genes. In other words, this embodiment of the method of the invention allows the identification of genes involved in the same protein cascade as the aberrantly expressed gene. Typically, the method of the invention will be a method performed in cell culture.

The method of the invention allows for the design of further medicaments that use other targets than the aberrantly expressed gene and are useful in the treatment of retinal diseases. For example, if a potential target downstream of the aberrantly expressed gene is indeed targeted by a medicament, the negative effect of the aberrantly expressed gene may be efficiently counterbalanced. Compounds modulating other genes in the cascade may have to be refined or further developed prior to administration as a medicament as described elsewhere in this specification.

Additionally, the invention relates to a method for identifying one or a plurality of genes the expression of which is modulated by the inhibition or decrease of the expression or activity of a (poly)peptide selected from the group consisting of the (poly)peptide of the invention or of a (poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 1 1 or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%ι, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. or by the inhibition or decrease of the expression of an mRNA encoding said

(poly)peptide, said modulation being indicative of a retinal disease, said method comprising the steps of:

(i) providing expression profiles of (1) a plurality of cells from or derived from retinal tissue of a subject suffering from a retinal disease; and (2) a plurality of cells from or derived from retinal tissue of a subject not suffering from a retinal disease; and

(ii) comparing the expression profiles (1) and (2), wherein a modulation of the expression is indicative of a candidate for a gene being involved in retinal diseases.

Also according to an alternative embodiment the present invention relates to a method for identifying one or a plurality of genes whose expression is modulated by the induction or enhancement of the expression or activity of a (poly)peptide selected from the group consisting of the (poly)peptide of the invention or of a

(poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(iv) being encoded by a nucleic acid molecule derived from the (poly) peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. or by the induction or enhancement of the expression of an mRNA encoding said (poly)peptide, said modulation being indicative of a retinal disease, said method comprising the steps of:

(i) providing expression profiles of (1) a plurality of cells from or derived from retinal tissue of a subject suffering from a retinal disease; and (2) a plurality of cells from or derived from retinal tissue of a subject not suffering from a retinal disease; and (ii) comparing the expression profiles (1) and (2), wherein a modulation of the expression is indicative of a candidate for a gene being involved in retinal diseases. In variation to the methods described herein above, one embodiment of the method of the invention compares the expression profiles of cells from a healthy subject and a subject suffering from a retinal disease. In this regard, isolated cells, including cells that are held in cell culture or even cell lines that autonomously grow in cell culture and that were originally derived from retinal tissue may be used to obtain samples for said method. By comparing the two expression profiles, differences in expression levels of genes involved in the retinal disease may be identified. As with the preceding embodiment, these genes may be part of a cascade involving the aberrantly expressed gene. Examples of such cascades are signaling cascades. Once genes are identified that are expressed at a different level in a retinal diseased, they may be tested for up-regulation or down-regulation by bringing them into contact with suitable test compounds. Again, these test compounds may then, with or without further development, be formulated into pharmaceutical compositions.

In a preferred embodiment, the method of the invention further comprising the steps of

(iii) determining at least one gene that is expressed at a lower or higher level in said cells from or derived from retinal tissue of a subject suffering from a retinal disease; and (iv) identifying a further compound that is capable of raising or lowering the expression level of said at least one gene.

This preferred embodiment of the invention requires that one of the genes the expression of which may directly or indirectly be lowered or increased by the expression of the aberrant gene is identified. Then, a further panel of test compounds may be tested for the capacity to increase or decrease the expression of said further gene. Compounds that are successfully tested would be prime candidates for the development of medicaments for the prevention or treatment of a retinal disease.

In another preferred embodiment, the method of the invention further comprising the steps of (iii) determining at least one gene that is expressed in a cell or a population of cells at a lower or higher level in the presence of said compound; and

(iv) identifying a further compound that is capable of raising or lowering the expression level of said at least one gene in a cell or a population of cells.

In variation of the previously discussed embodiment, this embodiment requires that at least one gene is identified by comparing the expression profiles of tissue or cells derived from a healthy subject and from a subject suffering from a retinal disease. Subsequently, at least one compound is identified that is capable of increasing or decreasing the expression of said gene.

Additionally, the invention relates to a method for identifying a protein or a plurality of proteins involved in the etiology of a retinal disease the activity of which is modulated by a (poly)peptide selected from the group consisting of the (poly)peptide of the invention or of a (poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1, 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. said method comprising the steps of

(i) providing said (poly)peptide; and

(ii) identifying a further protein that is capable of interacting with said (poly)peptide. One possible method to identify protein-protein interactions is the Yeast two-hybrid screen described by Golemis & Khazak (1997), Methods Mol Biol. 63:197-218.

Other well established methods in order to identify protein-protein interactions are co-immunoprecipitations or in vitro protein interaction assays like GST-pulldown assays (such as described in Stoss, Schwaiger, Cooper and Stamm (1999). J. Biol. Chem. 274r 10951 -10962). Further interaction assays are illustrated and described herein below. According to a preferred embodiment of the invention the identified (poly)peptide or (poly)peptide encoded by the identified gene forms a part of a signal cascade.

In a further preferred embodiment of the method of the invention said compound is a small molecule or a peptide derived from an at least partially randomized peptide library.

Libraries of small molecules suitable in the method of the invention are well known in the art and/or can be purchased form commercial distributors. The same holds true for the peptide libraries

In a further preferred embodiment, the method of the invention further comprises refining a compound identified, said method comprising the steps of the methods the invention and:

(1) identification of the binding sites of the compound to the (poly)peptide, the DNA or mRNA molecule by site-directed mutagenesis or chimeric protein studies;

(2) molecular modeling of both the binding site of the compound and the binding site of the DNA or mRNA molecule; and

(3) modification of the compound to improve its binding specificity for the protein, the DNA or mRNA.

All techniques employed in the various steps of the method of the invention are conventional or can be derived by the person skilled in the art from conventional techniques without further ado. Thus, biological assays based on the herein identified nature of the (poly)peptides may be employed to assess the specificity or potency of the drugs wherein the increase of one or more activities of the (poly) peptides may be used to monitor said specificity or potency. Steps (1) and (2) can be carried out according to conventional protocols. A protocol for site directed mutagenesis is described in Ling MM, Robinson BH. (1997) Anal. Biochem. 254: 157-178. The use of homology modeling in conjunction with site-directed mutagenesis for analysis of structure-function relationships is reviewed in Szkiarz¹ and Halpert (1997) Life Sci. 61 :2507-2520. Chimeric proteins are generated by ligation of the corresponding DNA fragments via a unique restriction site using the conventional cloning techniques described in Sambrook, Fritsch, Maniatis. Molecular Cloning, a laboratory manual. (1989) Cold Spring Harbor Laboratory Press. A fusion of two DNA fragments that results in a chimeric DNA fragment encoding a chimeric protein can also be generated using the gateway-system (Life technologies), a system that is based on DNA fusion by recombination. A prominent example of molecular modeling is the structure-based design of compounds binding to HIV reverse transcriptase that is reviewed in Mao, Sudbeck, Venkatachalam and Uckun (2000). Biochem. Pharmacol. 60: 1251-1265. For example, identification of the binding site of said drug by site-directed mutagenesis and chimerical protein studies can be achieved by modifications in the (poly)peptide primary sequence that affect the drug affinity; this usually allows to precisely map the binding pocket for the drug.

As regards step (2), the following protocols may be envisaged: Once the effector site for drugs has been mapped, the precise residues interacting with different parts of the drug can be identified by combination of the information obtained from mutagenesis studies (step (1)) and computer simulations of the structure of the binding site provided that the precise three-dimensional structure of the drug is known (if not, it can be predicted by computational simulation). If said drug is itself a peptide, it can be also mutated to determine which residues interact with other residues in the (poly)peptide of interest.

Finally, in step (3) the drug can be modified to improve its binding affinity or ist potency and specificity. If, for instance, there are electrostatic interactions between a particular residue of the (poly)peptide of interest and some region of the drug molecule, the overall charge in that region can be modified to increase that particular interaction.

Identification of binding sites may be assisted by computer programs. Thus, appropriate computer programs can be used for the identification of interactive sites of a putative inhibitor and the (poly)peptide by computer assisted searches for complementary structural motifs (Fassina, Immunomethods 5 (1994), 114-120). Further appropriate computer systems .for the computer aided design of protein and peptides are described in the prior art, for example, in Berry, Biochem. Soc. Trans. 22 (1994), 1033-1036; Wodak, Ann. N. Y. Acad. Sci. 501 (1987), 1-13; Pabo, Biochemistry 25 (1986), 5987-5991. Modifications of the drug can be produced, for example, by peptidomimetics and other inhibitors can also be identified by the synthesis of peptidomimetic combinatorial libraries through successive chemical modification and testing the resulting compounds. Methods for the generation and use of peptidomimetic combinatorial libraries are described in the prior art, for example in Ostresh, Methods in Enzymology 267 (1996), 220- 234 and Dorner, Bioorg. Med. Chem. 4 (1996), 709-715. Furthermore, the three- dimensional and/or crystallographic structure of activators of the expression of the (poly)peptide of the invention can be used for the design of peptidomimetic activators, e.g., in combination with the (poly)peptide of the invention (Rose, Biochemistry 35 (1996), 12933-12944; Rutenber, Bioorg. Med. Chem. 4 (1996), 1545-1558).

In accordance with the above, in a preferred embodiment of the method of the invention said compound is further refined by peptidomimetics.

In a further preferred embodiment, the method for identifying a protein further comprises modifying a compound identified or refined by the method as described herein above as a lead compound to achieve (i) modified site of action, spectrum of activity, organ specificity, and/or (ii) improved potency, and/or (iii) decreased toxicity (improved therapeutic index), and/or (iv) decreased side effects, and/or (v) modified onset of therapeutic action, duration of effect, and/or (vi) modified pharmakinetic parameters (resorption, distribution, metabolism and excretion), and/or (vii) modified physico-chemical parameters (solubility, hygroscopicity, color, taste, odor, stability, state), and/or (viii) improved general specificity, organ/tissue specificity, and/or (ix) optimized application form and route by (i) esterification of carboxyl groups, or (ii) esterification of hydroxyl groups with carbon acids, or (iii) esterification of hydroxyl groups to, e.g. phosphates, pyrophosphates or sulfates or hemi succinates, or (iv) formation of pharmaceutically acceptable salts, or (v) formation of pharmaceutically acceptable complexes, or (vi) synthesis of pharmacologically active polymers, or (vii) introduction of hydrophylic moieties, or (viii) introduction/exchange of substituents on aromates or side chains, change of substituent pattern, or (ix) modification by introduction of isosteric or bioisosteric moieties, or (x) synthesis of homologous compounds, or (xi) introduction of branched side chains, or (xii) conversion of alkyl substituents to cyclic analogues, or (xiii) derivatisation of hydroxyl group to ketales, acetales, or (xiv) N-acetylation to amides, phenylcarbamates, or (xv) synthesis of Mannich bases, imines, or (xvi) transformation of ketones or aldehydes to Schiffs bases, oximes, acetales, ketales, enolesters, oxazolidines, thiozolidines or combinations thereof; said method optionally further comprising the steps of the above described methods. The various steps recited above are generally known in the art. They include or rely on quantitative structure-action relationship (QSAR) analyses (Kubinyi, "Hausch-Analysis and Related Approaches", VCH Verlag, Weinheim, 1992), combinatorial biochemistry, classical chemistry and others (see, for example, Holzgrabe and Bechtold, Deutsche Apotheker Zeitung 140(8), 813-823, 2000).

The invention additionally relates to a method for inducing a retinal disease in a non-human mammal not suffering from a retinal disease, said disease being connected with the modulation of the expression of a (poly)peptide, comprising the step of contacting said mammal and preferably the eye of said mammal with an amount of a compound obtained by the method of the invention sufficient to change the normal expression or activity level of the target nucleic acid molecule or target (poly)peptide, said (poly)peptide selected being selected from the group consisting of the polypeptide of the invention or of a (poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said

(poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. This embodiment of the invention is particularly useful for mimicking factors/developments leading to the onset of the disease.

Induction of a retinal disease in accordance with the invention may comprise administration of an agent which is toxic in certain concentrations for said animal.

Said agent may also be an agent inducing expression of a gene product which is under the control of an above described inducible promoter.

The step of contacting said mammal and preferably the eye of said mammal with an amount of a compound obtained by the method of the invention relates to a test whether a compound identified by the method of the invention has the capacity to cure or to allay the retinal disease in said animal.

In a preferred embodiment of the method of the invention said that modulates the expression of said (poly)peptide is a small molecule, a peptide, an antibody or an aptamer that specifically binds said (poly)peptide.

The terms "small molecule" as well as "antibody" have been described herein above and bear the same meaning in connection with this embodiment.

In a preferred embodiment, the method as described herein above further comprises producing a pharmaceutical composition comprising the steps of the aforementioned methods and further the step of formulating the compound identified, refined or modified by the method of any of the preceding claims with a pharmaceutically active carrier or diluent. The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier and/or diluent. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions etc. Compositions comprising such carriers can be formulated by well known conventional methods. These pharmaceutical compositions can be administered to the subject at a suitable dose. Administration of the suitable compositions may be effected by different ways, e.g., by intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal or intrabronchiai administration. The dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. A typical dose can be, for example, in the range of 0.001 to 1000 μg (or of nucleic acid for expression or for inhibition of expression in this range); however, doses below or above this exemplary range are envisioned, especially considering the aforementioned factors. Generally, the regimen as a regular administration of the pharmaceutical composition should be in the range of 1 μg to 10 mg units per day. If the regimen is a continuous infusion, it should also be in the range of 1 μg to^" 10 mg units per kilogram of body weight per minute,^' respectively. Progress can be monitored by periodic assessment. Dosages will vary but a preferred dosage for intravenous administration of DNA is from approximately 106 to 1012 copies of the DNA molecule. The compositions of the invention may be administered locally or systemically. Administration will generally be parenterally, e.g., intravenously; DNA may also be administered directly to the target site, e.g., by biolistic delivery to an internal or external target site or by catheter to a site in an artery. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. Furthermore, the pharmaceutical composition of the invention may comprise further agents such as interleukins or interferons depending on the intended use of the pharmaceutical composition.

Presently there is no method described in the art by which retinal diseases described herein above, in particular AMD, are effectively treated in a causal therapy. Therapeutic approaches are e.g. laser-photokoagulation (thermal desolation of blood vessels), photodynamic therapie (PDT) or administration of PDT-agent Visudyne™ (Novartis Ophtalmics), of composition to lower cholesterol level or of vitamins compositions.

The invention also relates to a method for preventing or treating a retinal disease in a subject in need of such treatment, comprising the step of modulating the expression or activity level of a (poly)peptide in the retinal tissue of a subject, said (poly)peptide being selected from the group consisting of the (poly)peptide of the invention or of a (poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence; hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said

(poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, wherein said modulation results in an activity or expression level comparable to that in a subject not suffering from a retinal disease.

Further, the invention relates to a method of preventing or treating a retinal disease in a subject in need of such treatment, comprising the step of modulating the level (poly)peptide being selected from the group consisting of the (poly)peptide of the invention or of a (poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 1 1 or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. wherein said modulation results in an activity or expression level comparable to that in a subject not suffering from a retinal disease. The invention in a preferred embodiment relates to a method wherein such modulation is effected by administering the pharmaceutical composition obtained by the above described method of the invention.

In an other preferred embodiment the invention relates to a method, wherein such modulation is effected by introducing a nucleic acid sequence encoding the (poly)peptide of the invention into the germ line or into somatic cells of a subject in need thereof.

According to a preferred embodiment of the method of the invention said modulation is an is a inhibition or decrease.

An alternative preferred embodiment of the invention relates to a method wherein said modulation is an is a induction or enhancement.

In a further preferred embodiment of the method of the invention such modulation is effected by introducing the nucleic acid sequence recited above into the germ line or into somatic cells of a subject in need thereof.

In a more preferred embodiment of the method of the invention said retinal disease is a macular degeneration. In another preferred embodiment of the method of the invention said retinal disease is nightblindness.

More preferably, said macular degeneration is AMD (Age-related macular degeneration). Also in accordance with a preferred embodiment the invention said macular degeneration is Retinitis pigmentosa, Ushers syndrome, Best vitelliform macular dystrophy (Morbus Best), X-linked juvenile retinoschisis, North Carolina macular dystrophy, Sorsby fundus dystrophy, Doyne honeycomb retinal dystrbphy/Malattia leventinese or Stargardt disease (Morbus Stargardt).

In a further embodiment the invention relates to the use of an above described compound, a refined or modified compound, an aptamer or an antibody for the manufacture of a pharmaceutical composition for the prophylaxis or treatment of a retinal diseases

According to a preferred embodiment said retinal disease is a macular degeneration.

More preferably, said macular degeneration is AMD.

Also in accordance with a preferred embodiment the invention said macular degeneration is Retinitis pigmentosa, Ushers syndrome, Best vitelliform macular dystrophy (Morbus Best), X-linked juvenile retinoschisis, North Carolina macular dystrophy, Sorsby fundus dystrophy, Doyne honeycomb retinal dystrophy/Malattia leventinese or Stargardt disease (Morbus Stargardt).

According to another preferred embodiment said retinal disease nightblindness.

One embodiment of the invention relates to a kit comprising means and supplies for any of the preceding methods of diagnosing a retinal disease or a predisposition for a retinal disease of a subject, whereby said kit comprises at least one nucleic acid molecule of the invention, at least one vector of the invention, at least one host cell of the invention, at least one antibody or fragment or derivative thereof or aptamer of the invention, and/or reagents to proceed the methods of the invention. Said kit of the invention may be comprise one or more containers.

According to a preferred embodiment of the kit of the invention said retinal disease is nightblindness.

According to another preferred embodiment of the kit of the invention said retinal disease is a macular degeneration.

More preferably, said macular degeneration is AMD.

Finally, the present invention relates to the a method for diagnosing AMD or a predisposition to AMD comprising assessing nucleotide position 8 downstream of the 3' end of exon 1a (see also Figure 3d) for the occurrence of an adenine. Surprisingly, it was found in accordance with the invention that a substitution of adenine for cytosine in this position resulting in the loss of an RSAI restriction site (GTAC to GTAA) is correlated with the occurrence of AMD. The substitution may be analyzed by a variety of methods including restriction analysis including analysis of RFLPs, oligonucleotide hybridization techniques or contacting with antibodies, aptamers etc. that can differentiate between nucleic acid molecules bearing an A or a C in the recited position. On the basis of this finding and using various of the methods recited above pharmaceutical compositions may be produced that are useful in the prevention or treatment of AMD.

Further preferred values of percentage of identity at the amino acid level include for all corresponding embodiments of the invention at least 95 % and at least 98 %.

The figures show:

Figure 1 :

(a) nucleotide sequence of the cDNA of the variant 1/isoform 1 of WDR17 protein

(b) nucleotide sequence of the cDNA of the variant 2/isoform 2 of WDR17 protein

(c) nucleotide sequence of the variant 1of exon 1 of WDR17 protein

(d) nucleotide sequence of the variant 2 of exon 1 of WDR17 protein (e) nucleotide sequence of the variant 3 of exon 1 of WDR17 protein.

Figure 2:

(a) amino acid sequence of the (poly)peptide of the variant 1/isoform 1 of

WDR17 protein (b) amino acid sequence of the (poly)peptide of the variant 2/isoform 2 of

WDR17 protein

Figure 3:

(a) nucleotide sequence of the cDNA of the variant 1/isoform 1 of NETO1 protein

(b) nucleotide sequence of the cDNA of the variant 2/isoform 2 of NETO1 protein

(c) nucleotide sequence of the cDNA of the variant 3/isoform 3 of NETO1 protein (d) NETO1 genomic structure nucleotide sequence of genomic structure of NETO 1 protein. Exon sequences (bold) are depicted with flanking intron sequences. Exon 5 represents the last exon in isoform 1 of the NETO1 protein and is spliced out in isoform 2 and isoform 3.

Figure 4:

(a) amino acid sequence of the (poly)peptide of the variant 1/isoform 1 of NETO1 protein

(b) amino acid sequence of the (poly)peptide of the variant 2/isoform 2 of NETO1 protein

(c) amino acid sequence of the (poly)peptide of the variant 3/isoform 3 of NETO1 protein

Figure 5: nucleotide sequence of the cDNA of the Protein kinase A203 protein

Figure 6: amino acid sequence of the (poly)peptide of the Protein kinase A203 protein

Figure 7:

(a) nucleotide sequence of the cDNA of the Protein kinase MAK A194 protein (b) nucleotide sequence of the cDNA of variant 1 of the Protein kinase MAK A194 protein

(c) nucleotide sequence of the cDNA of variant 2 of the Protein kinase MAK A194 protein

(d) nucleotide sequence of the cDNA of variant 3 of the Protein kinase MAK A194 protein

(e) nucleotide sequence of the cDNA of variant 4 of the Protein kinase MAK A194 protein

Figure 8: (a) amino acid sequence of the (poly)peptide of Protein kinase MAK A194 protein

(b) amino acid sequence of the (poly)peptide of variant 1 of Protein kinase MAK A194 protein

(c) amino acid sequence of the (poly)peptide of variant 2 of Protein kinase MAK A194 protein

(d) amino acid sequence of the (poly)peptide of variant 3 of Protein kinase MAK A194 protein (e) amino acid sequence of the (poly)peptide of variant 4 of Protein kinase MAK A194 protein

Figure 9: (a) nucleotide sequence of the cDNA of the variant 1 of protein A105 protein

(b) nucleotide sequence of the cDNA of the variant 2 of protein A105 protein

(c) nucleotide sequence of the cDNA of the variant 3 of protein A105 protein

(d) nucleotide sequence of the cDNA of the variant 4 of protein A105 protein

(e) nucleotide sequence of the cDNA of the variant 5 of protein A105 protein (f) nucleotide sequence of the cDNA of the variant 6 of protein A105 protein

(g) nucleotide sequence of the cDNA of the variant 7 of protein A105 protein (h) nucleotide sequence of the cDNA of the variant 8 of protein A105 protein

Figure 10: (a) amino acid sequence of the (poly)peptide of the variant 1 of protein A105 protein

(b) amino acid sequence of the (poly)peptide of the variant 2 of protein A105 protein

(c) amino acid sequence of the (poly)peptide of the variant 3 of protein A105 protein

(d) amino acid sequence of the (poly)peptide of the variant 4 of protein A105 protein

(e) amino acid sequence of the (poly)peptide of the variant 5 of protein A105 protein (f) amino acid sequence of the (poly)peptide of the variant 6 of protein A105 protein (g) amino acid sequence of the (poly)peptide of the variant 7 of protein A105 protein (h) amino acid sequence of the (poly)peptide of the variant 8 of protein A105 protein Figure 11 : nucleotide sequence of the cDNA of protein A106 protein

Figure 12: amino acid sequence of the (poly)peptide of protein A106 protein

Figure 13: nucleotide sequence of the cDNA of C12orf3variants protein

Figure 14: amino acid sequence of the (poly)peptide of C12orf3variants protein

Figure 15:

15 a: RT-PCR analysis of WDR17 expression in different tissues. 15 b: Northern blot analysis with a WDR17 cDNA probe

Figure 16:

16 a: Northern blot analysis of NETO1 expression with an isoform 1 specific probe 16 b: RT-PCR analysis of NETO 1 expression in different tissues

Figure 17:

RT-PCR analysis of the expression of WDR17, NETO1 , Protein A105, Protein kinase A203, Protein A106, C12orf3variants and Protein kinase MAK A 194 in human tissues

Examples

The following examples illustrate the invention. These examples should not be construed as limiting: the examples are included for purposes of illustration and the present invention is limited only by the claims.

EXAMPLE 1 Isolation of WDR17 cDNA

The publically accessible UniGene dataset, release no. 113 (June, 2000), at the National Center for Biotechnology Information (NCBI) at the National Institutes of Health (NIH), Bethesda, Maryland (http://www.ncbi.nlm.nih.gov/UniGene/) was searched for human EST clusters consisting of ESTs exclusively derived from retina cDNA libraries or for EST clusters with an enrichment of retina ESTs, defined by a portion of retina ESTs that is greater than 30% of the total. One of the 1241 entries meeting these criteria, Hs.175480 (changed to Hs.333256 release no. 146 from December, 2001), contained a 241 bp 5' read and a 219 bp 3' read EST sequence from a cDNA clone isolated from the Soares retina N2b4HR cDNA library (ze40a11). Reverse transcription (RT)-PCR using oligonucleotides designed on the basis of the 5' EST, A176F (5'-TCCTCAGAACTACTGCAAAG-3') and A176R (5'-CTCAAGTGGATTTCAGCAG-3'), obtained a strong 165 bp fragment in retina and a weak band in cerebellum RNA but not in RNA from lung, heart, liver or uterus.

The 2248 bp insert of IMAGE cDNA clone ze40a11 was completely sequenced with walking primer technology. To extend the 5' end sequence of the corresponding gene termed WDR17 (WD repeat domain 17), 5' rapid amplification of cDNA ends (RACE) was performed on human retina Marathon-ready cDNA (BD Biosciences Clontech, Palo Alto, USA) using the gene-specific reverse primer A176R and the adaptor AP1 Primer (5^*-CCATCCTAATACGACTCACTATAGGGC- 3'). Amplification products were ligated into the pGEM^®-T Easy Vector (Promega GmbH, Mannheim, Germany), transformed in E.coli and screened by colony hybridization with a γ-³²P-ATP-endlabeled oligonucleotide A176R3 (5- GCTTCCTTCAGTCTTTCCTC-3'). Sequence analysis of the positive clones revealed an additional 901 bp of 5' cDNA sequence. Furthermore, the working draft sequence of genomic clone RP11-637O11 (GenBank Ace. No. AC022988) harbouring the known cDNA sequence was analyzed with various gene and exon prediction programs included in the NIX WWW tool (http://www.hgmp.mrc.ac.uk/Registered/Webapp/nix/). Primer oligonucleotide A176F5 (5'-GTCCCAGGTAAGGCAAGTG-3') designed on the basis of one of the predicted exons and reverse primer A176R7 (5- ACAGTATCCACACAAGTTCC-3') located in the known WDR17 cDNA sequence amplified a specific 1869 bp cDNA fragment, thus extending the transcript by another 1326 bp.

Two alternative 5' ends of WDR17 transcripts were identified by screening a human retinal cDNA library with a 777 bp probe obtained by RT-PCR with primer oligonucleotides A176F5 and A176R9 (5'-AACATGCCTGGAGCACTGG-3'). Clone 3/1/2 comprised a 231 bp 5' end that when assembled with the known WDR17 sequence yields a 4706 bp transcript with a conserved polyadenylation signal at nucleotide position 4678 bp. This cDNA, named isoform 1 , contains an open reading frame (ORF) of 3978 bp with a first potential in frame translation initiation codon, ATG, starting 10 nucleotides downstream. The protein predicted from the ORF consists of 1322 amino acids, resulting in a calculated molecular mass of 147.73 kDa and an isoelectric point of 6.01.

Clone 6/1/1 contained an alternative 184 bp 5' end that partially verlapped with clone 3/1/2. Added to the known WDR17 sequence a 4659 bp isoform 2 was obtained containing an ORF of 3915 bp with the first potential in frame translation initiation codon starting 181 nucleotides downstream. Translation of the cDNA leads to a truncated 1298 amino acid WDR17 protein lacking the first 25 N-terminal residues of the putative protein deduced from isoform 1.

EXAMPLE 2 Genomic organization and chromosomal location of WDR17 The WDR17 cDNA sequences were aligned to the Working' raft sequence of genomic clone RP11-637O11 using the BLASTN program at NCBI (http://www.ncbi.nlm. nih.gov/cgi-bin/BLAST/nph-blast?Jform=1). This identified a total of 31 exons ranging from 21 bp to 700 bp. Note that an internal splice donor sites in exon 1 is used in isoform 1. The putative translation start codon ATG is Jocated in exon 2 in isoform 1 and in exon 3 in isoform 2. The termination codon TGA is found in exon 31.

The WDR17 gene is located in chromosome 4q34.1 as determined by FISH mapping clones (http://genome.ucsc.edu/cgi-bin/hgBlat?hgsid=1394330).

EXAMPLE 3 Alternative splicing of WDR17 Two alternative splicing events were identified. Skipping of exon 2 was observed in the retina cDNA clone 6/1/1 leading to an altered ORF with an alternative first start codon in exon 3 (see above). In addition, in-frame skipping of exon 13 (165 bp) was found in RT-PCR amplification products obtained with oligonucleotide primers A176F4 (5'-CCGGGTAATGAAGGTGTTAT-3') located in exon 9 and A176R7 located in exon 14. The deletion leads to the loss of 56 internal amino acids and generates a novel codon at the exon 12/exon 14 boundary encoding an asparagine residue. Therefore, transcripts lacking exon 13 can be translated into a putative 1270 amino acid protein isoform.

EXAMPLE 4 Expression analysis

RT-PCR analysis using oligonucleotide primers A176F4 and A176R7 identified a strong 647 bp product in human retina and testis (Figure 15a). The weaker 482 bp signals correspond to alternatively spliced cDNA fragments without exon 13. Weak to faint bands were also observed in other tissues including brain, fetal brain, spinal cord, bone marrow, thymus, colon, skeletal muscle and uterus. Northern blot analysis was performed with total RNA isolated using the guanidinium thiocyanate method. Each lane containing 10 μg of total RNA from retina, lung, cerebellum and uterus was electrophoretically separated in the presence of formaldehyde. A 1611 bp DNA fragment from the 3' end of WDR17 was obtained by RT-PCR amplification with ^"primer pair AΪ76F/AT76R5 (5'-GCAATeCTTCTCeCAACC-3') and was used as a probe for filter hybridization in 0.5 mM sodium phosphate buffer, pH 7.2; 7% SDS, 1 mM EDTA at 58°C. A single -7-8 kb transcript was identified exclusively in retina. The results of our expression analysis provide evidence that WDR17 is predominantly active in the human retina and testis.

EXAMPLE 5 Nucleotide and protein database analyses Nucleotide homology searches with the full length cDNA sequence of WDR17 did not find significant sequence identities to known mRNA sequences in the public databases.

The putative WDR17 protein was analzyed for specific motifs using the Simple Modular Architecture Research Tool (SMART) at the European Molecular Biology Laboratory (http://smart.embl-heidelberg.de/). A total of eleven conserved WD40 domains were identified in the N-terminal half of the protein (position 72-112; 159- 202; 205-252; 255-298; 383-422; 425-465; 468-509; 511-550; 555-595; 598-638; 641-681). Sequence homology to other known proteins was restricted to the region containing the WD40 repeat. WD40 repeats have been found in both eukaryotic and prokaryotic organisms and typically consist of about 40 residues, each containing a central Trp-Asp motif. WD40 repeats are implicated in a wide variety of crucial functions including protein- protein interaction.

EXAMPLE 6 Mutation analysis

Preliminary mutational analyses of the human WDR17 gene were done using the Denaturing Gradient Gel-Electrophoresis (DGGE) method (Fischer and Lerman, 1983). DGGE-segments for all protein encoding exons were designed based on their melting profile. In one case, the exon was split in two segments (exon9-1 and exon 9-2) to facilitate detection of sequence changes. Due to more than 3 melting domains per encoding region, 3 exons were unsuitable for DGGE mutation analysis, thus resulting in 29 remaining WDR17 DGGE-amplicons. Primer binding sites were chosen in such a way that each amplicon contains at least 14 additional nucleotides upstream of the 5'-splice site and 4 nucleotides downstream of the 3'- splice site, respectively. To improve the detection of sequence changes in" the amplified products, a GC-ciamp has been added to the 5'-end of either the forward or reverse primer. DGGE analyses of the WDR17 gene was done using genomic DNA samples of AMD patients and using non AMD samples as control. Fragments containing mutations, indicated by DGGE band shift patterns, were verified by sequencing using the non-GC-clamp primer. Preliminary analyses revealed a G/A polymorphism at pos. 87 in exon 29, resulting in an aminoacid change from alanin to threonin at pos. 26 in exon 29, e.g. pos. 1214 of the entire protein, respectively.

EXAMPLE 7 Isolation of NETO1 cDNA The publically accessible UniGene dataset, release no. 113 (June, 2000), at the National Center for Biotechnology Information (NCBI) at the National Institutes of Health (NIH), Bethesda, Maryland (http://www.ncbi.nlm.nih.gov/UniGene/) was searched for human EST clusters consisting of ESTs exclusively derived from retina cDNA libraries or for EST clusters with an enrichment of retina ESTs, defined by a portion of retina ESTs that is greater than 30% of the total. One of the 1241 entries meeting these criteria, Hs.60563 comprised three overlapping 3' read ESTs derived from retinal tissue. To isolate the full length cDNA sequence of the corresponding human NETO1 gene, we completely sequenced the 1665 bp insert of retina I.M.A.G.E clone 360239 (GenBank ace. no. AA013001). To recover additional sequences, a human retinal cDNA library was screened with a [D-32P]- dCTP labeled 201 bp fragment obtained by PCR amplification from I.M.A.G.E. clone 360239 (RZPD, Berlin, Germany) with primers A124F (S'-CTT CTG GCC CCT CTC TTC-3') and A124R (5'-TGG GAT AGT TGG GAG AGG-3'). Several positive clones were isolated with clone A124/6/1 extending the cDNA sequence 73 bp in 5' and 111 bp in the 3' direction. The assembled 1849 bp nucleotide sequence, designated isoform 1 (sNETOI), contains an 573 bp open reading frame (ORF) with a first potential in-frame translation start codon, ATG, 103 bp downstream of the 5' end. The proposed start codon lies in a sequence context following the Kozak rule. An in-frame stop codon is located three nucleotides upstream of the most 5' end of the cDNA. The transcript encodes a 135 amino acid (aa) sequence with a classical signal peptide of 21 aa giving rise to a mature 114 aa protein with a calculated molecular weight of 15.4 kDa. The results of 5'-RACE experiments on human retina Marathon-ready cDNA (BD Biosciences Clontech, Palo Alto, USA) with a first round of PCR performed with the gene-specific reverse primer A124R followed by a nested PCR reaction with primer A124R5 (5-CCG TTC CTT TCT TGG TTG CC-3') indicated the presence of an additional NETO1 transcript with an alternative 5' sequence. Cloning and sequencing of several 5'-RACE products identified two subsets of cDNA fragments at similar abundance. One group of cDNAs corresponded to the 5' end of clones 360239 and A124/6/1 with no further extension. A second group of 5' RACE products, however, showed a sequence divergence upstream of nucleotide position 117 (nucleotide numbering according to clone A124/6/1). Translation of the alternativ transcript results in 11 novel N-terminal amino acids forming a predicted signal peptide of 22 residues. An in-frame stop codon is present 12 bp upstream of the proposed alternative start codon.

To isolate the complete 3' end of NETO1 , a survey for ESTs was conducted in working draft genomic sequences (Ace. No. AC091138). This revealed a cluster of ESTs derived from neural tissue including retina mapping about 30 kb downstream of the known sequence (e.g. GenBank Ace. Nos BF958898, BG497575, BF698373; H84237). To connect these ESTs with the 5'end of NETO1, RT-PCR with reverse primer A124R7 (5-TGG ATA AAG GCA GTG GAA TG-3') was used in conjunction with forward primers A124F and A124F3 (5 -TTA ACA CCT CTC GAC CCT G-3') derived from the alternative 5' regions of NETO1, respectively. Specific products of 1741 bp and 1816 bp were obtained and sequenced. In addition, 3' RACE was applied on human retina Marathon-ready cDNA (BD Biosciences Clontech, Palo Alto, USA) with a first PCR reaction with gene-specific primer A124F4 (δ'-GTG GCT GTG TAT GAT GGA AG-3') followed by a nested PCR using primer A124F5 (5'-ACA GAG ATG CCC ACA CAG C-3') and extended the 3' sequences by 125 bp. Full length NETO1 transcripts of 2328 bp (isoform 2) and 2519 bp (isoform 3) were assembled both encoding distint precursor proteins which after the predicted posttranslational cleavage of the individual leader peptides result in an identical mature protein of 511 aa with a molecular weight of 57.8 kDa.

EXAMPLE 8 Genomic organization and chromosomal location of NETO1 Alignment of NETO1 cDNA isoforms 1 , 2 and 3 to genomic sequences indicated the presence of a total of 12 exons spanning more than 120 kb on chromosome 18q22-q23. The exon/intron splice junctions of all 12 exons follow the conserved GT/AG consensus rule (see figure 3d). NETO1 transcripts of isoform 2, 3 and 1 are produced by the usage of two transcription start sites and alternative splicing of exon 5, respectively. Transcription of isoform 2 and 3 is alternatively initiated from exon 1b or 1a and skipping of exon 5 to generate an ORF that terminates in exon 11. Exon 12 represents a spliced 3' untranslated exon. The truncated isoform 1 comprises exon 1b, exon 2 through 4 and uses the conserved 3' splice acceptor site of exon 5 which leads to an in-frame stop codon only 2 bp downstream of the splice site.

EXAMPLE 9 Expression analysis of NETO1

Initial Northern blot analysis using a probe specific to isoform 1 detected a 2.0 kb transcript in human retina but not in cerebellum and uterus (Fig. 16A). To further determine the tissue distribution of the NETO1 isoforms, we performed RT-PCR assays (Fig. 16B). The analysis with primers in exon 4 and in isoform 1 -specific exon 5 confirmed that the truncated form is exclusively expressed in the human retina. PCR amplification with primers located in the leader exons (exon 1a and 1b) and exon 8 showed that isoform 2 is present in the retina only while isoform 3 is additionally transcribed at lower levels in adult and fetal brain tissue. This suggests a tissue-specific utilization of the two transcriptional start sites in exon 1a and 1b (Fig. 3d). Whereas transcription initiation in exon 1a occurs in neural tissues, the internal transcription start site in exon 1 b is exclusively used in the retina indicating the presence of neural- and retina-specific promoter elements upstream of exon 1a and 1b, respectively.

EXAMPLE 10 Domain structure of NETO1

Hydropathy analysis of the amino acid sequence deduced from isoform 2 and 3 of the full length NETO1 transcripts revealed an internal stretch of 23 hydrophobic residues extending from position 321-343 of the mature protein. This hydrophobic region is flanked by several charged amino acids on the C-terminal side resembling membrane-spanning domains of type I transmembrane proteins.

The N-terminal 320 amino acids of NETO1 constitute a putative extracellular domain composed of two different conserved motifs. This includes two tandemly arranged CUB domains, named after the complement subcomponents C1s/C1r, an embryonic sea urchin protein Uegf, and the bone morphogenic protein-1 (BMP1). The two CUB domains comprise 112 and 116 aa and both contain the four highly conserved cysteines predicted to form two disulfide bridges (C1-C2, C3-C4). C- terminal to the CUB domains, a single cysteine-rich repeat was found with significant homology to the low density lipoprotein (LDL)-receptor class A (LDLa) repeat initially described in the LDL receptor.

The truncated protein deduced from isoform 1 consists only of the N-terminal copy of the CUB domains followed by a NFTPE pentapeptide. The C-terminal glutamic acid is unique to this isoform. The lack of the transmembrane and cytosolic regions implicates that isoform 1 encodes a soluble variant, termed sNETOI , which is specificall secreted by retinal cells.

EXAMPLE 11 Mutation analysis

Preliminary mutational analyses of the human NETO1 gene were done using the denaturing high-performance liquid chromatography (dHPLC) method. Analyses were done using genomic DNA samples of AMD patients. Fragments containing mutations were verified by sequencing. Preliminary analyses revealed a C/A polymorphism at pos. 8 downstream to the 3'-end of exon 1a (see figure 3d). The C to A transition results in a lost of a Rsal restriction site (GTAC to GTAA) and the polymorphism was analysed in non AMD control samples by restriction analysis with Rsal. The C to A transition was only found in AMD patients.

Further mutational analyses of the human NETO1 gene were performed using the Denaturing Gradient Gel-Electrophoresis (DGGE) method (Fischer and Lerman, 1983). Preliminary analyses revealed an A/C polymorphism 8 bp upstream to the 5'-end of exon 1b in the 5' untranslated region and a G to A transition at pos. 1719 of NETO1 isoform 3 leading to a valin to isoleucine aminoacid change at position 477 in isoform 3.

References

Banks CN, Hutton WK. Blindness in New South Wales: an estimate of the prevalence and some of the contributing causes. Aust J Ophthalmol 9:285-288 (1981).

Bohler C, Nielsen PE, Orgel LE. Template switching between PNA and RNA oligonucleotides. Nature. 376(6541 ):578-81 (1995).

Bressler NM, Bressler SB. Preventative ophthalmology. Age-related macular degeneration. Ophthalmology 102:1206-1211 (1995). Bressler NM, Bressler SB, Fine SL. Age-related macular degeneration. Surv Ophthalmol 32:375-413 (1988).

Bressler SB, Bressler NM, Fine SL, Hillis A, Murphy RP, Oik RJ, Patz A. Natural course of choroidal neovascular membranes within the foveai avascular zone in senile macular degeneration. Am J Ophthalmol 93:157-163 (1982). Davis LG, Kuehl M, Kuehl MW, Battey JF. Basic methods in molecular biology. Sec. Ed. Elsevier (1990).

Feeney L. Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies. Invest Ophthalmol Vis Sci 17:583-600 (1978). Feeney-Burns L, Ellersieck MR. Age-related changes in the ultrastructure of Bruch's membrane. Am J Ophthalmol 100:686-697(1985).

Finn PJ, Gibson NJ, Fallon R, Hamilton A, Brown T. Synthesis and properties of DNA-PNA chimeric oligomers. Nucleic Acids Res. 24: 3357-3363 (1996).

Fischer SG, Lerman LS. DNA fragments differing by single base-pair substitutions are separated in denaturing gradient gels: correspondence with melting theory. Proc Natl Acad Sci U S A. 80(6): 1579-83 (1983).

Gass JD. Drusen and disciform macular detachment and degeneration. Arch Ophthalmol 90:206-217 (1973).

Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol 63: Suppl:1-139(1967).

Ghafour IM, Allan D, Foulds WS. Common causes of blindness and visual handicap in the west of Scotland. Br J Ophthalmol 67: 209-213 (1983).

Gossen M, Bonin AL, Freundlieb S, Bujard H. Inducible gene expression systems for higher eukaryotic cells. Curr Opin Biotechnol. 5(5):516-20 (1994). Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 89(12):5547-5551 (1992).

Gotoh M, Hasebe M, Ohira T, Tosu M. [Gene diagnosis with an affinity sensor, BIACORE-principle and applications]. Rinsho Byori. 45(3):224-8 (1997). Japanese. Green WR, McDonnell PJ, Yeo JH. Pathologic features of senile macular degeneration. Ophthalmology 92:615-27 (1985).

Grey RH, Burns-Cox CJ, Hughes A. Blind and partial sight registration in Avon. Br J Ophthalmol 73:88-94(1989). Heiba IM, Elston RC, Klein BE, Klein R. Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study. Genet Epidemiol 11 :51-67 (1994).

Hogan MJ, Alvarado J. Studies on the human macula. IV. Aging changes in Bruch's membrane. Arch Ophthalmol 77:410-420(1967). Hyman LG, Lilienfeld AM, Ferris FL, Fine SL. Senile macular degeneration: a case- control study. Am J Epidemiol 118:213-227 (1983).

Hyman L. Epidemiology of eye disease in the elderly. Eye 1 : 330-341 (1987).

Jalkanen M, Nguyen H, Rapraeger A, Kurn N, Bernfield M. Heparan sulfate proteoglycans from mouse mammary epithelial cells: localization on the cell surface with a monoclonal antibody. J Cell Biol. 101(3):976-984 (1985).

Jalkanen M, Rapraeger A, Saunders S, Bernfield M. Cell surface proteoglycan of mouse mammary epithelial cells is shed by cleavage of its matrix-binding ectodomain from its membrane-associated domain. J Ceil Biol. 105:3087-96 (1987). Jensen KK, Orum H, Nielsen PE, Norden B. Kinetics for hybridization of peptide nucleic acids (PNA) with DNA and RNA studied with the BIAcore technique. Biochemistry 36(16):5072-5077 (1997).

Joyner A. Gene Targeting, A Practical Approach, Second edition, Oxford University Press (1999). Klein R, Klein BE, Franke T. The relationship of cardiovascular disease and its risk factors to age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 100:406-414 (1993).

Koch T, Hansen HF, Andersen P, Larsen T, Batz HG, Otteson K, Orum H. Improvements in automated PNA synthesis using Boc/Z monomers. J Pept Res. 49(1):80-8 (1997).

Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256(5517) :495-497 (1975).

Leibowitz HM, Krueger DE, Maunder LR, Milton RC, Kini MM, Kahn HA, Nickerson RJ, Pool J, Colton TL, Ganley JP, Loewenstein Jl, Dawber TR. The Framingham Eye Study monograph: An ophthalmological and epidemiological study of cataract, glaucoma, diabetic retinopathy, macular degeneration, and visual acuity in a general population of 2631 adults, 1973-1975. Surv Ophthalmol 24(Suppl): 335- 610 (1980).

Le Mouellic H, Lallemand Y, Brulet P. Targeted replacement of the homeobox gene Hox-3.1 by the Escherichia coli lacZ in mouse chimeric embryos. Proc Natl Acad Sci U S A. 87(12):4712-4716 (1990). Maguire P, Vine AK. Geographic atrophy of the retinal pigment epithelium. Am J Ophthalmol 102:621-625 (1986).

Mantero G, Zonaro A, Albertini A, Bertolo P, Primi D. DNA enzyme immunoassay: general method for detecting products of polymerase chain reaction. Gin Chem. 37(3):422-429 (1991).

Mayer RJ, Walker JH, eds. Immunochemical methods in cell and molecular biology. Academic Press, London (1987).

Melani C, Rivoltini L, Parmiani G, Calabretta B, Colombo MP. Inhibition of proliferation by c-myb antisense oligodeoxynucleotides in colon adenocarcinoma cell lines that express c-myb. Cancer Res. 51:2897-2901 (1991)

Meyers SM, Zachary AA. Monozygotic twins with age-related macular degeneration. Arch Ophthalmol 106:651-653 (1988).

Paetkau ME, Boyd TA, Grace M, Bach-Mills J, Winship B. Senile disciform macular degeneration and smoking. Can J Ophthalmol 13:67-71 (1978). Pauleikhoff D, Harper CA, Marshall J, Bird AC. Aging changes in Bruch's membrane. A histochemical and morphologic study. Ophthalmology 97:171- 178(1990).

Piguet B, Wells JA, Palmvang IB, Wormald R, Chisholm IH, Bird AC. Age-related Bruch's membrane change: a clinical study of the relative role of heredity and environment. Br J Ophthalmol 77:400-403 (1993).

Sambrook et al., Molecular Cloning, A Laboratory Manual, 2^nd edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

Sarks SH. Ageing and degeneration in the macular region: a clinico-pathological study. Br J Ophthalmol 60:324-341 (1976). Schuler GD. Pieces of the puzzle: expressed sequence tags and the catalog of human genes. J Mol Med. 75(10):694-8 (1997)

Seddon JM, Ajani UA, Mitchel BD. Familial aggregation of age-related maculopathy. Am J Ophthalmol 123: 199-206 (1997).

Smith and Johnson. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene 67:31-40 (1988)

Silvestri G, Johnston PB, Hughes AE. Is genetic predisposition an important risk factor in age-related macular degeneration? Eye 8:564-568 (1994).

Sobol RE, Astarita RW, Chisari FV, Griffiths JC, Royston I. Use of immunoglobulin light chain analysis to detect bone marrow involvement in B-cell neoplasms. Clin Immunol Immunopathol. 24(1):139-144 (1982).

Sobol RE, Dillman RO, Collins H, Griffiths JC, Green MR, Royston I. Applications and limitations of peripheral blood lymphocyte immunoglobulin light chain analysis in the evaluation of non-Hodgkin's lymphoma. Cancer 56(8):2005-2010 (1985).

Sperduto RD, Hiller R. Systemic hypertension and age-related maculopathy in the Framingham Study. Arch Ophthalmol 104:216-219 (1986). Steinecke, Ribozymes, Methods in Cell Biology 50, Galbraith et al. eds Academic Press, Inc.: 449-460 (1995).

The Eye Disease Case-Control Study Group. Risk factors for neovascular age- related macular. Arch Ophthalmol 110:1701-1708 (1992). Tijssen P.; Burden, RH and von Knippenburg (Eds). Practice and theory of enzyme immuno-assays. Elsevier, Amsterdam, Vol. 15 (1985).

Verma R.S.;Babu A. Human chromosomes; Manual of basic techniques. New York, Pergamon Press (1989).

Veselkov AG, Demidov W, Frank-Kamenetskii MD, Nielsen PE. PNA as a rare genome-cutter. Nature. 379(6562):214 (1996).

Wahl RL, Parker CW, Philpott GW. Improved radioimaging and tumor localization with monoclonal F(ab')2. J Nucl Med. 24(4):316-25 (1983).

Weiler J, Gausepohl H, Hauser N, Jensen ON, Hoheisel JD. Hybridisation based DNA screening on peptide nucleic acid (PNA) oligomer arrays. Nucleic Acids Res. 25(14):2792-9 (1997).

Yap M, Weatherill J. Causes of blindness and partial sight in the Bradford Metropolitan District from 1980 to 1985. Ophthalmic Physiol Opt 9:289-292 (1989).

Claims

Claims

1. A nucleic acid molecule comprising a nucleotide sequence selected form the group consisting of:

(a) a nucleotide sequence encoding the preferably mature form of a protein comprising the amino acid sequence as depicted in figure 4 or of a precursor thereof;

(b) a nucleotide sequence comprising of the DNA sequence as depicted in figure 3;

(c) a nucleotide sequence hybridizing with the complementary strand of a nucleotide sequence as defined in (a) or (b) under stringent hybridization conditions and coding for a (poly)peptide having the same function as the (poly)peptide having the amino acid sequence depicted in 4;

(d) a nucleotide sequence encoding a polypeptide derived from the (poly)peptide encoded by a nucleotide sequence of (a) or (b) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (a) or (b), whereby said (poly)peptide has the same function as the

(poly)peptide having the amino acid sequence depicted in figure 4;

(e) a nucleotide sequence encoding a protein having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (a) or (b), whereby said (poly)peptide has the same function as the (poly)peptide having the amino acid sequence depicted in figure 4;

(f) a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (a) or (b) and encoding a

(poly)peptide having the same function as the (poly)peptide having the amino acid sequence depicted in figure 4; (g) a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (a) or (b) and encoding a (poly)peptide having the same function as the (poly)peptide having the amino acid sequence depicted in figure 4; and

(h) a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of (a) to (g) ;

2. A nucleic acid molecule of at least 15 nucleotides in length hybridizing specifically with the nucleic acid molecule of claim 1 or with a complementary strand thereof.

3. A vector comprising the nucleic acid molecule of claim 1.

4. A vector comprising a nucleic acid molecule of claim 3, wherein the nucleic acid molecule is DNA.

5. The vector of claim 3 or 4 which is an expression vector wherein said nucleic acid molecule is operatively linked to one or more expression control sequences allowing the transcription and optionally translation in prokaryotic and/or eukaryotic host cells.

6. A host cell containing the vector of any one of claims 3 to 5 or the nucleic acid molecule of claim 1.

7. The host cell of claim 6 which is a bacterial, insect, fungal, plant or animal cell.

8. The host cell of claim 6 which is a human cell or derived from a human cell line.

9. A method for the production of a (poly)peptide or an immunologically active or functional fragment thereof comprising culturing the host cell of anyone of claims 6 to 8 under conditions allowing the expression of the (poly)peptide and recovering the produced (poly)peptide from the culture.

10. A (poly)peptide or an immunologically active or functional fragment thereof encoded by the nucleic acid molecule of claim 1 or obtainable by the method of claim 9.

1 1. The (poly)peptide of claim 10 which is glycosylated, phosphorylated, and/or amidated.

12. An antibody or fragment or derivative thereof or an aptamer specifically recognizing the (poly)peptide of claim 10 or 1 1 or a fragment or epitope thereof, wherein said fragment or epitope has the same structural conformation as the corresponding portion of the native (poly)peptide.

13. The antibody of claim 12, which is a monoclonal antibody.

14. A transgenic non-human mammal whose somatic and germ cells comprise at least one nucleic acid sequence encoding a functional form of the

(poly)peptide of claim 10 or 11 , wherein said nucleic acid sequence optionally has been modified, said modification being sufficient to increase the amount or activity of said functional (poly)peptide having the same or essentially the same function as the (poly)peptide having the amino acid sequence depicted in figure 4.

15. A transgenic non-human mammal according to claim 14, wherein the modification is activation or enhancement of the expression of said nucleic acid sequence or leads to the increment of the synthesis of the corresponding protein.

16. A transgenic non-human mammal whose somatic and germ cells lack a nucleic acid sequence encoding a functional form of the (poly)peptide of claim 10 or 11 or show a deficiency in the activity or expression of a (poly)peptide of claim 10 or 11.

17. The transgenic non-human mammal according to anyone of claims 14 to 16, wherein said nucleic acid sequence was introduced into the non-human mammal or an ancestor thereof, at an embryonic stage.

18. A method for the diagnosis of a retinal disease or a predisposition for a retinal disease of a subject comprising the steps of:

(a) contacting a sample isolated from said subject or from cells isolated from said subject or in a subject, suspected to contain at least one isoform or mutated form of the (poly)peptide of claim 10 or 1 1 or of a

(poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10,

12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(iv) being encoded by a nucleic acid molecule derived from the

(poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poiy)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, -most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by- a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, with a receptor specific for said (poly)peptide; and (b) detecting or quantitating the amount of said protein in said sample; wherein the presence or amount of said isoform or mutated form is indicative of a retinal disease.

19. The method according to claim 18, wherein the presence or the amount of said isoforms or mutated forms is quantitated using an aptamer or an antibody or an antigen-binding portion of said aptamer or antibody that specifically binds to said isoforms or mutated forms.

20. The method according to claim 19, wherein said antibody or antibody binding portion is or is derived from a human antibody or a humanized antibody.

21. The method according to claim 19 or 20, wherein the antibody is the antibody or fragment or derivative thereof of claim 12 or 13.

22. The method of claim 21 , wherein said fragment of said antibody is a Fab-, a F(ab')₂- and said derivative is an scFv-fragment.

23. The method of any of claims 19 to 22, wherein the aptamer or the antibody or fragment or derivative of said aptamer or antibody is detectably labeled.

24. The method of any one of claims 19 to 23 wherein said (poly)peptide is quantitated in an in situ test.

25. The method of any one of claims 19 to 24 further comprising the step of normalizing the amount of (poly)peptide detected in said sample against a corresponding (poly)peptide detected in a sample from a healthy subject or cells derived from a healthy subject.

26. A method of diagnosing a retinal disease or a predisposition for a retinal disease of a subject, comprising the step of analyzing at least one nucleic acid molecule or quantitating the amount of at least one RNA in a sample of said subject, wherein (a) . said at least one nucleic acid sequence or RNA encodes an amino acid sequence consisting of:

(aa) an amino acid sequence as depicted in any of figures 2, 4, 6, 8, 10, 12 or 14;

(ab) an amino acid sequence that is at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence of (aa);

(ac) the amino acid sequence of (aa) with at least one conservative amino acid substitution;

(ad) an amino acid sequence that is an isoform of the amino acid sequence-o any-of (aa).to (ac);iand

(ae) an amino acid that is encoded by a DNA molecule the complementary strand of which hybridizes under stringent conditions to the DNA molecule encoding the amino acid sequence of (aa), (ac) or (ad); (b) said at least one RNA is transcribed from the DNA sequence as depicted in any of figures 1 , 3, 5, 7, 9; 1 1 or 13 or a degenerate variant thereof; and or (c) said at least one nucleic acid molecule has the sequence depicted in any one of figures 1 , 3, 5, 7, 9, 11 or 11 or a sequence hybridizing under stringent conditions to the complementary strand thereof.

27. The method according to claim 26, wherein the amount of the said RNA is quantitated using a nucleic acid probe which is:

(a) the nucleic acid molecule having the sequence as depicted in any of figures 1 , 3, 5, 7, 9, 1 1 or 13 or a degenerate variant thereof;

(b) a nucleic acid molecule having a sequence that encodes the amino acid sequence as depicted in any of figures 2, 4, 6, 8, 10, 12 or 14, whereby optionally said amino acid sequence has at least one conservative amino acid substitution;

(c) a nucleic acid sequence that hybridizes under stringent conditions to the complementary strand of the nucleic acid molecule encoding the amino acid sequence of (a) or (b); (d) . a fragment of at least 15 nucleotides in length and being part of the sequence of any of (a) to (c); and

(e) a nucleic acid probe comprising a sequence that specifically hybridizes under physiological conditions to the nucleotide sequence of: (i) the cDNA derived from the RNA transcribed from the DNA sequence as depicted in any of figures 1 , 3, 5, 7, 9, 11 or 13; (ii) a DNA sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the DNA sequence of (i); (iii) a nucleic acid sequence that encodes^the amino-aeid sequence as depicted in any of figures 2, 4, 6, 8, 10, 12 or 14 with at least one conservative amino acid substitution; (iv) a nucleic acid sequence that encodes an amino acid sequence that is at least 65%, preferably at least 80%, especially at least

. 90%, most preferred at least 99% identical to the amino acid sequence of (iii); (v) a nucleic acid sequence that encodes the amino acid sequence of (iii) with at least one conservative amino acid substitution; (vi) a nucleic acid sequence that hybridizes in 2xSSC, 0.1% SDS at 65°C to the DNA molecule encoding the amino acid sequence of (iii), (iv) or (v); and (vii) a fragment of at least 15 nucleotides in length and being part of the sequence of (i) to (vi).

28. The method of claim 26 or 27, wherein said nucleic acid or RNA is obtained from retinal tissue.

29. The method of any one of claims 26 to 28 further comprising the step of normalizing the amount of RNA against a corresponding RNA from a healthy subject or cells derived from a healthy subject.

30. A method for identifying a compound that modulates the translation level of a (poly)peptide selected from the group consisting of the (poly)peptide of claim 10 or 11 or a (poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule

function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several_, amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive . amino acids of a protein encoded by a nucleotide sequence of (i) or

(ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. said method comprising the steps of:

(a) contacting a DNA encoding said (poly)peptide under conditions that permit the translation of said (poly)peptide with a test compound; and

(b) assessing the level of said (poly)peptide wherein a modulated level of the (poLy)peptide relative -t the-level of translation, .obtained n the absence of the test compound is indicative of the modulating activity of said compound at the translation level.

1. A method for identifying a compound that specifically binds to or interacts with a (poly)peptide of claim 10 or 11 or a (poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or

14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(iv) being encoded by a nucleic acid molecule derived from the

(poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, . especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or

(ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or

(iii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under-<stringent conditions>with arprobeΛπaving a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. said method comprising the steps of:

(a) providing said (poly)peptide;

(b) contacting one or a plurality of compounds with said (poly)peptide; and (c) identifying one or a plurality of compounds that is capable of binding to or interacting with said (poly)peptide.

32. The method of claim 31 , wherein said binding results in a modulation of the activity of said (poly)peptide.

33. A method for identifying a compound that modulates the level of an mRNA encoding a (poly)peptide wherein said (poly)peptide is the preferably mature form of a (poly)peptide selected from the group consisting of the (poly)peptide of claim 10 or 11 or a (poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or

14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the ;(:poly)peptide encoded by a. nucleotide sequence of (i) or (ii) by way .of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or

(ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or

(iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, in a cell or a tissue, said method comprising the steps of (i) contacting a DNA giving rise to said mRNA under conditions that permit transcription of said mRNA with a test compound; and (ii) assessing the level of transcribed mRNA wherein a modulated level of the mRNA relative to the level of transcription obtained in the absence of the test compound is indicative of the modulating activity of said compound at the translation level.

A method for identifying a compound that modulates -the -expression of a (poly)peptide in a cell or a tissue, the (poly)peptide being selected from the group consisting of the (poly)peptide of claim 10 or 11 or of a (poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or

14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 1 1 or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the

(poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%), most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or

(ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or

(iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein, said ^(poly)peptide . has , the same function as the

(poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. said method comprising the steps of: (i) contacting a transgenic non-human mammal according to any one of claims 14 to 16 with a test compound, and

(ii) assessing the level of a (poly)peptide wherein a modulated expression of a (poly)peptide relative to the level of expression obtained in the absence of the test compound is indicative of the modulating activity of said compound at the expression level.

35. The method according to anyone of claims 30 or 34, wherein the test compound prevents or ameliorates a retinal disease in a transgenic non- human mammal according any of claims 14 to 16.

36. The method of any of claims 30 to 35, wherein said modulation is an inhibition or decrease of the expression.

37. The method of any of claims 30 to 35, wherein said modulation is an induction or enhancement of the expression.

38. A method for identifying one or a plurality of genes the expression of which is modulated by the inhibition or decrease of the expression or activity of a (poly)peptide selected from the group consisting of the (poly)peptide of claim 10 or 1 1 or of a (poly)peptide being the preferably mature form of a

(poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or

14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in Jigure , ,.5,. ^ 9,rt,1 or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, or by the inhibition or decrease of the expression of an mRNA encoding said (poly)peptide, said modulation being indicative of a retinal disease, said method comprising;the.steps of:

(i) contacting a plurality of cells with a compound that inhibits or decreases the expression or activity of said (poly)peptide under conditions that permit the expression of said (poly)peptide in the absence of said compound, and (ii) comparing gene expression profiles of said cells in the presence and in the absence of said compound.

39. A method for identifying one or a plurality of genes the expression of which is modulated by the induction or enhancement of the expression or activity of a (poly)peptide selected from the group consisting of the (poly)peptide of claim 10 or 11 or of a (poly)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or

14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the . (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded.^, by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, or by the induction or enhancement of the expression of a mRNA encoding said (poly)peptide, said modulation being indicative of a disease, said method comprising the steps of: (i) contacting a plurality of cells with a compound that inhibits or decreases the expression of said (poly)peptide under conditions that permit the expression or activity of said (poly)peptide in the absence of said compound, and (ii) comparing gene expression profiles of said cells in the presence and in . the absence of said compound.

40. A method for identifying one or a plurality of genes the expression of which is modulated by the inhibition or decrease of the expression or activity of a (poly)peptide selected from the group consisting of the (poly)peptide of claim 10 or 1 1 or of a (poly)peptide being the preferably mature form of a

(poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or

14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure ty δ, 7 9^ 1- or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the

(poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or

(ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or

(iii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or

(ii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, or by the inhibition or decrease o the expression of an mRNA encoding said (poly)peptide, said modulation being indicative of a retinal disease, said method comprising the steps of:

(i) providing expression profiles of

(1) a plurality of cells from or derived from retinal tissue of a subject suffering from a retinal disease; and (2) a plurality of cells from or derived from retinal tissue of a subject not suffering from a retinal disease; and (ii) comparing the expression profiles (1) and (2), wherein a modulation of the expression is indicative of a candidate for a gene being involved in retinal diseases.

41. A method for identifying one or a plurality of genes whose expression is modulated by the induction or enhancement of the expression or activity of a

(poly)peptide selected from the group consisting of the (poly)peptide of claim

10 or 11 or of a (poly)peptide being the preferably mature form of a

(poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid . molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino -acid sequence encoded y the .nucleotide sequence:, of (i). or.

(ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of -(ii) or

(iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. or by the induction or enhancement of the expression of an mRNA encoding said (poly)peptide, said modulation being indicative of a retinal disease, said method comprising the steps of:

(i) providing expression profiles of

(1 ) a plurality of cells from or derived from retinal tissue of a subject suffering from a retinal disease; and

(2) a plurality of cells from or derived from retinal tissue of a subject not suffering from a retinal disease; and

(ii) comparing the expression profiles (1 ) and (2), wherein a modulation of the expression is indicative of a candidate for a gene being involved in retinal diseases.

42. The method of anyone of claims 38 to 41 further comprising the steps of

(iii) determining at least one gene that is expressed at a lower or higher level in< said -cells from- or derived from retinal tissue of a subject suffering from a retinal disease; and (iv) identifying a further compound that is capable of raising or lowering the expression level of said at least one gene.

43. The method of anyone of claims 38 to 41 further comprising the steps of (iii) determining at least one gene that is expressed in a cell or a population of cells at a lower or higher level in the presence of said compound; and

(iv) identifying a further compound that is capable of raising or lowering the expression level of said at least one gene in a cell or a population of cells.

44. A method for identifying a protein or a plurality of proteins involved in the etiology of a retinal disease the activity of which is modulated by a (poly)peptide selected from the group consisting of the (poly)peptide of claim 10 or 1 1 or of a (poly)peptide being the preferably mature form of a

(poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or

14; (ii) being encoded by the nucleic acid molecule having the sequence . depicted in figure 1 , 5, 7, 9, 11 or 13;

(iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the

(poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the - (poly)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or

(ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or

(iii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or

(ii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); or (viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, said method comprising the steps of (i) providing said (poly)peptide; and (ii) . identifying a further protein that is capable of interacting with said

(poly)peptide.

45. The method of any of claims 38 to 44 wherein said identified (poly)peptide or (poly)peptide encoded by the identified gene forms a part of a signal cascade.

46. The method of any one of claims 30 to 37 or 42 to 45 wherein said compound is a small molecule or a peptide derived from an at least partially randomized peptide library.

47. The method of any one of claims 30 to 37 or 42 to 46, further comprising refining the compound identified, said method comprising the steps of the method of any one of 30 to 37 or 42 to 46 and:

(1 ) identification of the binding sites of the compound to the

(poly)peptide, the DNA or mRNA molecule by site-directed mutagenesis or chimeric protein studies; (2) molecular modeling of both the binding site of the compound and the binding site of the DNA or mRNA molecule; and (3) modification of the compound to improve its binding specificity for the protein, the DNA or mRNA.

48. The method of any one of claims 30 to 35 or 42 to 47, wherein said compound is further refined by peptidomimetics.

49. The method of any one of claims 30 to 37 or 42 to 48 further comprising modifying the compound identified or refined as a lead compound to achieve: (i) modified site of action, spectrum of activity, organ specificity, and/or

(ii) improved potency, and/or

(iii) decreased toxicity (improved therapeutic index), and/or (iv) decreased side effects, and/or (v) modified onset of therapeutic action, duration of effect, and/or (vi) modified pharmakinetic parameters (resorption, distribution, metabolism and excretion), and/or (vii) modified physico-chemical parameters (solubility, hygroscopicity, color, taste, odor, stability, state), and/or (viii) improved general specificity, organ/tissue specificity, and/or (ix) optimized application form and route by

(i) esterification of carboxyl groups, or (ii) esterification of hydroxyl groups with carbon acids, or (iii) esterification of hydroxyl groups to, e.g. phosphates, pyrophosphates or sulfates or hemi succinates, or

(iv) formation of pharmaceutically acceptable salts, or

(v) formation of pharmaceutically acceptable complexes, or (vi) synthesis of pharmacologically active polymers, or

(vii) introduction of hydrophylic moieties, or

(viii) introduction/exchange of substituents on aromates or side chains, change of substituent pattern, or (ix) modification by introduction of isosteric or bioisosteric moieties, or

(x) synthesis of homologous compounds, or

(xi) introduction of branched side chains, or

(xii) conversion of alkyl substituents to cyclic analogues, or

(xiii) derivatisation of hydroxyl group to ketales, acetales, or (xiv) N-acetylation to amides, phenylcarbamates, or

(xv) synthesis of Mannich bases, imines, or

(xvi) transformation of ketones or aldehydes to Schiffs bases, oximes, acetales, ketales, enolesters, oxazolidines, thiozolidines or combinations thereof; said method optionally further comprising the steps of the method of the method of any one of claims 30 to 37 and 42 to 48.

50. A method for inducing a retinal disease in a non-human mammal not suffering from a retinal disease, said disease being connected with the modulation of the expression of a (poly)peptide, comprising the step of contacting said mammal and preferably the eye of said mammal with an amount of a compound obtained by the method of anyone of claims 30 to 37 and 42 to 49 sufficient to change the normal expression or activity level of the target nucleic acid molecule or target (poly)peptide, said (poly)peptide selected being selected from the group consisting of the polypeptide of claim

10 or 11 or of a (poiy)peptide being the preferably mature form of a (poly)peptide

(i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by.the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the

(poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or

(ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii);

(vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or

(iii), wherein said (poly)peptide has the same function as the . (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences.

51. The method according to claim 50 wherein said compound that modulates the expression of said (poly)peptide is a small molecule, a peptide, an antibody or an aptamer that specifically binds said (poly)peptide.

52. The method of any one of claims 30 to 37 or 42 to 48, further comprising producing a pharmaceutical composition comprising the further step of formulating the compound identified, refined or modified by the method of any of the preceding claims with a pharmaceutically active carrier or diluent.

53. A method for preventing or treating a retinal disease in a subject in need of such treatment, comprising the step of modulating the expression or activity level of a (poly)peptide in the retinal tissue of a subject, said (poly)peptide being selected from the group consisting of the (poly)peptide of claim 10 or 11 or of a (poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14;

(ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1, 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (iv) being encoded by a nucleic acid molecule derived from the

(poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid . sequence encoded by the nucleotide sequence of (i) or

(ii), whereby said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or

(iii), wherein said (poly)peptide has the same . function as the (poly)peptide of (i) or (ii);

(vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the

(poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences. wherein said modulation results in an activity or expression level comparable to that in a subject not suffering from a retinal disease.

54. A method of preventing or treating a retinal disease in a subject in need of such treatment, comprising the step of modulating the level of mRNA encoding a (poly)peptide in the retinal tissue of a subject, said (poly)peptide being selected from the group consisting of the (poly)peptide of claim 10 or 11 or of a (poly)peptide being the preferably mature form of a (poly)peptide (i) having the amino acid sequence depicted in figure 2, 6, 8, 10, 12 or 14; (ii) being encoded by the nucleic acid molecule having the sequence depicted in figure 1 , 5, 7, 9, 11 or 13; (iii) being encoded by a nucleic acid molecule having a sequence hybridising with the complementary strand of the nucleic acid molecule of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); , . .

(iv) being encoded by a nucleic acid molecule derived from the (poly)peptide encoded by a nucleotide sequence of (i) or (ii) by way of substitution, deletion and/or addition of one or several amino acids of the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (v) having an amino acid sequence at least 65%, preferably at least 80%, especially at least 90%, most preferred at least 99% identical to the amino acid sequence encoded by the nucleotide sequence of (i) or (ii), whereby said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vi) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having at least 12 consecutive nucleotides of a nucleotide sequence of (ii) or (iii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); (vii) being encoded by a nucleotide sequence obtainable by screening an appropriate library under stringent conditions with a probe having a nucleotide sequence encoding a fragment of at least 4 consecutive amino acids of a protein encoded by a nucleotide sequence of (i) or (ii), wherein said (poly)peptide has the same function as the (poly)peptide of (i) or (ii); or

(viii) being encoded by a nucleotide sequence which is degenerate as a result of the genetic code to a nucleotide sequence of any one of the above-recited sequences, wherein said modulation results in an activity or expression level comparable to that in a subject not suffering from a retinal disease.

55. The method of claims 53 or 54, wherein such modulation is effected by administering the pharmaceutical composition obtained by the method of claim 47.

56. The method of claim 53 or 54, wherein such modulation is effected by introducing a nucleic acid sequence encoding the (poly)peptide recited in claim 18 into the germ line or into somatic cells of a subject in need thereof.

57. The method of any one of claims 53 to 56 wherein said modulation is an is a inhibition or decrease.

58. The method of any one of claims 53 to 56 wherein said modulation is an is a induction or enhancement.

59. The method of any one of any of the preceding claims wherein said retinal disease is a macular degeneration.

60. The method of claim 59 wherein said macular degeneration is AMD (Age- related macular degeneration).

61. Use of a compound of any one of the 30 to 35, 46, a compound refined or modified by the method of any one of the claims 47 to 49, or an aptamer or an antibody of any of claims 12, 13 or 20 to 23 for the manufacture of a pharmaceutical composition for the prophylaxis or treatment of a retinal diseases.

62. The use of claim 61 whereby said retinal disease is a macular degeneration or nightblindness.

63. The use of claim 62 whereby said macular degeneration is AMD.

64. A kit comprising means and supplies for diagnosing a retinal disease or a predisposition for a retinal disease in a subject whereby said kit comprising at least one nucleic acid molecule according to claim 1 or 2, at least one vector according to anyone of claims 3 to 5, at least one host cell according to anyone of claims 6 to 8, at least one antibody or fragment or derivative thereof or aptamer according to claim 12 or 13 and/or reagents to proceed the methods of any one of claims 18 to 30.

65. The kit of claim 64 whereby said retinal disease is a macular degeneration or nightblindness.

66. The kit of claim 65 whereby said macular degeneration is AMD.

67. A method for diagnosing AMD or a predisposition to AMD comprising assessing nucleotide position 8 downstream of the 3' end of exon 1a for the occurrence of an adenine.