AU666142B2 - Viral recombinant vectors for expression in muscle cells - Google Patents
Viral recombinant vectors for expression in muscle cells Download PDFInfo
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- AU666142B2 AU666142B2 AU27902/92A AU2790292A AU666142B2 AU 666142 B2 AU666142 B2 AU 666142B2 AU 27902/92 A AU27902/92 A AU 27902/92A AU 2790292 A AU2790292 A AU 2790292A AU 666142 B2 AU666142 B2 AU 666142B2
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- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
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- C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
- C12N2710/10341—Use of virus, viral particle or viral elements as a vector
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Abstract
Non-replicatable viral recombinant vectors which are recognizable by muscle cell receptors, and furthermore modified by an insertion nucleic acid coding for a polypeptide sequence to be expressed in said muscle cells, are used to obtain a drug for treating muscle cell diseases or diseases which, by virtue of their location in the body, are accessible to the products of the expression of the above mentioned nucleotide sequence, as secreted by said muscle cells. A method for producing said vectors, vectors such as those described above, and their use in pharmaceutical compositions are also provided.
Description
OPI DATE 27/04/93 AOJP DATE 24/06/93 APPLN. ID 27902/92 PCT NUMBER PCT/FR92/00898 AU9227902
I
ITr I 2I L' DINL, V LI a (PCT) (51) Classification internationale des brevets 5 (11) Nuni~ro de publication internationale: WVO 93/06223 C12N 15/12, 9/61 8/0A (43) Date de publication internationale: Iler avril 1993 (01.04.93) (21) Num~ro de ]a demnande internationale: PCT/FR92/00898 (74) Mandataires: GUTMANN, Ernest etc. Ernest Gutmann- Yves Plasseraud 67, boulevard Haussmann, F- (22) Date de d~p~t international: 25 septembre 1992 (25.09.92) 75008 Paris (FR).
Donn~es relatives a la prioriti (81) Etats d~sign~s: AU, CA, JP, US, brevet europ~en (AT, BE, 91/11947 27 septembre 1991 (27.09.91) FR CH, DE, DK, ES, FR, GB, OR, IE, 1T, LU, MC, NL, S E).
(71) D~posant (pour tous les Elats d6sign~s sauf US): CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE Publi~e [FR/FR]; 15, quai Anatole-France, F-75067 Ai'ec rapport de recherche internationale.
Paris Avani I'expiration du d~lai pr~vu pour la modifcation des revendications, sera republike si de relies modifications sont (72) Inventeurs; et repiies.
Inventeurs/D~posants (US seuletnent) PERRICAUDET, Michel [FR/FR]; 20, residence du Moulin, F-28150 Quarville I3RIAND, Pascale [FR/FR]; 10, rue du Docteur-Roux, F-750 15 Paris STRATFORD-PER- RICAUDET, Leslie [FR/FR]; 20, residence du Moulin, F-28 150 Ouarville (FR).
666142'I1mi (54) Title: VIRAL RECOMBINANT VECTORS FOR EXPRESSION IN MUSCLE CELLS (54)Titre.: VECTEURS RECOMBINANTS VIRAUX POUR L'EXPRESSION DANS DES CELLULES MUSCULAIRES (57) Abstract Non-replicatable viral recombinant vectors which are recognizable by muscle cell receptors, and furthermore rinodified by an insertion nucleic acid coding for a polypeptide sequence to be expressed in said muscle cells, are used to obtain a drug for treating muscle cell diseases or diseases which, by virtue of their location in the body, are accessible to the products of the expression of the above mentioned nucleotide sequence, as secreted by said muscle cells. A method for producing said vectors, vectors such as those described above, and their use in pharmaceutical compositions are also provided.
(57) Abr~lg6 II ASKIVE Sous 0 I.'J 1 4 1 I1113IiHl LINCAIRI X
A
2.0 9.4 17IG A. LINEAR PLASMID j LAIROVIRUS GIRNtM B. ADENOVIRUS GENOME RSI A l B.TREATED WITH Cla I IRI1 AIl C..1 UNIT 360 pb tB it I 7-- Ad.RISV-Ilgal L'invention concerne Ilutilisation de vecteurs recoin- I binants d'origine virale, non r~plicables, et susceptibles "I 3 60 Pb C d'6tre reconnus par les r~ceptetirs de cellules musculaires, ces vecteurs 6tant en outre modif ies par un acide nucl~ique d'insertion codant pour une sequence polypeptidique dont l'expression dans lesdites cellules musculaires cst recherch~e, pour Ilobtention d'un m~dicament destin6 au traitement de pathologies affectant les cellules musculaires ou de pathologies dont la localisation dans l'organisme les rendent accessibles aux produits de l'expression de la sequence nucl~otidique stis-mentionn~e secrkt~s par lesdites cellules musculaires. L'invention concerne 6galement un proc~d6 d'obtention de ces vecteurs, et des vecteurs tels que d~crits ci-dessus et leur utilisation dans des compositions pharmaceutiques.
RECOMBINANT VIRAL VECTORS FOR EXPRESSION IN MUSCLE
CELLS
The invention relates to recombinant vectors of viral origin which contain a nucleotide sequence coding for a specific polypeptide, and their use for the expression of this polypeptide in muscle cells. The invention also relates to a procedure for producing these vectors, as well as to their uses, in particular as medicines in the field of muscle diseases.
The hitherto unresolved problem of the direct diffusion of a gene towards a specific tissue is an obstacle to the development of gene therapy in the field of muscle diseases.
The various attempts to modify muscle tissue performed hitherto consist mainly of that involving fusion of muscle cells with a host cell (Salminen, A. et al., Hum. Gene Ther. 2, 15-26 (1991); Partridge, T.A. et al., Nature 337, 176-179 (1989), and that involving direct injection of DNA into the muscles (Wolff, J.A. et al., Science 247, 1465_1468 (1991); Acsadi, New Biol. 3, 71-81 (1991)).
The method proceeding by the fusion in mice of precursors of muscle cells derived from a normal donor with muscle fibers of a host (Partridge, T.A. et al., mentioned above) has been carried out with success and this cellular therapy has been the subject of preliminary trials in children. However, this approach seems to present too many disadvantages to be applicable to the treatment of muscle diseases. In fact, since the migratory capacities of the precursor cells are reduced to a few millimeters, the cellular implantation of these latter would necessitate millions of injections requiring hours of anaesthesia. Inevitably, there would be the risk of immunological problems leading to rejection phenomena occurring, as in the case of very many grafts. In addition, the treatment of Duchenne's muscular dystrophy (DMD) not only requires making contact with the skeletal muscles but also with the myocardial cells; the difficulties likely to be encountered in implanting precursors of muscle cells in the myocardium can easily be imagined. Consequently, cellular therapy hardly seems to be appropriate for the treatment of diseased cells showing such dissemination in the organism.
Gene therapy by direct in vivo introduction of nucleic acids into the interior of organs is an attractive method on account of its simplicity, but its development is confronted with a number of obstacles. In particular, the -2expression of genes in the muscles remains localised at the site of injection (Wolff, J.A. et al., mentioned above) and seems to be of quite limited duration, particularly in cardiac muscle (Acsadi, G. et al., mentioned above).
The aim of the present invention is precisely to make possible the introduction of a very large number of nucleic acids into a considerable number of muscle cells (up to 50% or more) of a human or animal organism, whether these muscle cells be those of skeletal muscle or those of the myocardium.
The present invention relates more particularly to the transport of nucleic acids to target muscle cells by the blood, while protecting these nucleic acids against attack by various blood constituents.
SAnother aim of the present invention is to make available to the public pharmaceutical compositions which make possible the treatment of muscle diseases, and more particularly genetic diseases of the muscle system, or also diseases, the localization of which in the organism makes them accessible to the expression products of the above-mentioned nucleic acids, these products being secreted by the said muscle cells.
The present invention follows from the discovery made by the inventors of the fact that beta-galactosidase activity is found in many tissues after injection into mice of recombinant vectors of viral origin, more particularly of adenoviral origin, into the genome of which the gene coding for beta-galactosidase has been inserted. Such tissues include the lungs, liver, intestine, heart and the skeletal muscles. The expression of the gene for beta-galactosidase is constant with time, since the proportion of blue-coloured cells (colour obtained subsequent to gene expression) in the muscle tissue is more or less the same from one month to the next.
Figure 1 shows an example of the construction of a recombinant vector according to the invention and corresponding to a type adenovirus, into the genome of which the gene for beta-galactosidase has been inserted under the control of the RSV promoter.
In one aspect, the present invention provides a method for delivering to human or animal muscle cells a non-replicative recombinant viral vector comprising a nucleic acid sequence encoding a polypeptide sequence, said method comprising the step of: a. id injecting intravenously or intraarterially said recombinant vector, wherein S' said nucleic acid sequence is under the control of a promoter recognised by polymerases of said muscle cells and wherein said polypeptide is expressed in said muscle cells.
-3- The invention also provides a recombinant vector comprising a defective genome of an adenovirus, comprising all of the essential sequences necessary for the encapsidation of said adenovirus, and in which is inserted a recombinant nucleic acid sequence under the control of a promoter recognised by polymerases of human or animal muscle cells.
The adenoviruses, in particular the human adenoviruses type 2 or represent particularly preferred vectors in the framework of the present invention by virtue in particularly of the large size of the foreign DNA fragment which it is possible to insert into the genome of these viruses.
Advantageously, the above-mentioned nucleic acid insert is included in a defective genome of an adenovirus, this genome lacking essential sequences necessary for the replication of these adenoviruses, and more particularly the EA and EB transactivators; nonetheless, this genome preferentially includes all of those essential sequences necessary for the encapsidation of these adenoviruses.
The promoter used may be an endogenous promoter for example, an early or late promoter of the adenovirus used) or an exogenous promoter.
It will be advantageous to have recourse to strong promoters, for example one having about the same strength as the promoter contained in the LTR (Long Terminal Repeat) of RSV (Rous Sarcoma Virus).
As examples of other promoters whose use may be considered, mention should be made of the promoter of the IE gene of CMV (cytomegalovirus) the MMTV (Mouse Mammary umor Virus) inducible promoters or metallothionine promoters.
The strength of the promoter which is used may be estimated in assays similar to those which are described in the examples which follow, for example by repting the promoter under study in the vectors of these examples by the promoter contained in the LTR of RSV and by the evaluation of the intensity of expression of the marker obtained, an intensity which can then be compared with that obtained with the promoter of LTR of RSV.
The amoun tof vectors administered to the organism is advantageously chosen so as to -overwhelm the immune system of the organism into which they are injected 951123 ,p:\opcr\jms,27902-92.cl,3 Advantageously, the route of adminstration selected in the framework of the present invention is the intravenous or intraarterial route.
Among the diseases affecting muscle cells mentioned above, mention may be made of genetic diseases such as muscular dystrophy.
Consequently, the nucleic acid inserted into the genome of the viral vector and the diffusion of which into the muscle mass is desired, comprises a nucleotide sequence coding for a polypeptide capable of treating the disease in question, and more particularly of playing the role in the muscle cell of the polypeptide normally present in a healthy cell, but the deficiency of which is due either to an abnormally low level or the complete failure of the production of this polypeptide, or to an error in its amino acid sequence which results from genetic anomalies in its coding nucleotide sequence.
Vectors according to the invention used to produce a medicine designed for the treatment of muscular dystrophy are more particularly characterized in that the nucleic acid insert is constituted by all or part of a healthy gene for dystrophin. The introduction of the entire gene for dystrophin or even of any part of this gene which codes for a polypeptide conserving an activity similar to that of the whole protein can be carried out in accordance with a method identical with that described hereafter for the introduction of the gene for beta-galactosidase.
As examples of diseases other than muscle diseases, susceptible to treatment in the framework of the present invention, mention may be made of the thromboses originating from infarctuses or also phlebites.
Vectors according to the invention used to produce a drug designed for the treatment of thromboses and for the prevention of infarcts and phlebites are more particularly characterized in that the nucleic acid insert comprises a nucleotide sequence coding for a thrombolytic substance. The latter sequence is advantageously preceded by a signal sequence which codes for a peptide signal which ensures the secretion of the thrombolytic substance outside the muscle cell.
The invention also relates to any recombinant vector characterized in that it is constituted of the defective genome of an adenovirus comprising, nonetheless, all of the essential sequences necessary for the encapsidation of this adenovirus, and into which is inserted a recombinant nucleic acid, the diffusion of which is desired in the muscle mass, this nucleic acid being placed under the control of a promoter capable of being recognized by the polymerases of the muscle cells, in particular by the strong promoter of the E1A early region r f the genome of the adenoviruses.
A preferrei recombinant ve.tor of the invention is characterized in that this recombinant nucleic acid is constituted by all or part of the gene for dystrophin.
The invention also relates to pharmaceutical compositions consisting one or more recombinant vectors such as those described above, in combination with a pharmaceutically acceptable vehicle.
The subject of the invention is also a procedure for producing the recombinant vectors described above which comprises, after the construction stage itself of these vectors by the introduction of the nucleic acid insert into their genome, a transformation step of transformable cell lines of higher eukaryotes (particularly of human or animal origin), themselves carrying a distinct nucleotide sequence capable of complementing the part of the genome of the adenovirus essential for the replication thereof and which the above-mentioned vector lacks, the said distinct sequence being preferably .ncorporated into the genome of the cells of the said cell line.
As a preferred example of such cell lines, mention should be made of line 293, a human embryonic kidney line which contains, integrated into its genome, the first eleven percent of the lefthand end of the genome of an This portion complements defective recombinant viruses which bear deletions in this region. Such a production procedure is more particularly described in the European patent application No. 0 185 573 of 20/11/85.
After transformation of these cell lines, the vectors which are thus multiplied are recovered and purified.
The present invention will be illustrated more particularly with the aid of the detailed description which follows of the construction of recombinant adenovirus vectors comprising the gene coding for betagalactosidase, and of the properties of this adenovirus vector.
1. Construction of the recombinant adenovirus, Ad-RSV-beta-gal, by means of in vivo recombination.
This recombinant adenovirus was constructed by homologous recombination between a suitable plasmid and the genome of a type adenovirus. In this construction, the gene for beta-galactosidase is placed under the control of the RSV (Rous Sarcoma Virus) promoter. The plasmid pAdRSV "B t a contains the PvuII segment of the lefthand end -f the Ad5 (segment situated between the positions 0 and 1.3 of the plasmid in Figure 1) comprising the inverted terminal repeat, the origin of replication, encapsidation signals and the amplifier Ela. This fragment is followed by a nlslacZ gene (described in Bonnerot, C. et al., Proc. Natl, Acad. Sci. USA, 1987, 84, 6795-6799) which codes for beta-galactosidase, and by a fragment of the adenovirus Ad5 situated between the positions 9.4 and 17 of the plasmid of Figure 1.
The values of the positions 1.3, 9.4 and 17 indicated above are units indicating the number of base pairs included within these fragments, one unit representing 360 base pairs.
The Ad5 sequence situated between the above-mentioned positions 9.4 and 17 allows recombination with the adenovirus d1324 treated by the restriction enzyme Clal (corresponding to a deletion mutant E3; the deletion being made between the positions 78.4 and 84.3 of the genome of the adenovirus shown in Figure after transfection of 293 cells (human embryonic kidney cells transformed by the adenvirus and mentioned above) in order to generate the recombinant vector Ad-RSV-betagal. The nlslacZ gene is controlled by the RSV LTR promoter and possesses the polyadenylation signal of the SV40 virus. The recombinant virus thus obtained is incapable of replicating on account of the deletion of the El genes.
2. Study of the transfer of the gene to the organs of the mouse through the intermediary of the adenovirus.
Four dal, old Balb/C mice are given an intravenous injection of microliters <of highly purified recombinant adenovirus Ad-RSV-betagal (109 plaque-forming units PFU/ml) the organs were excised 15 days after the injection and treated with 4% paraformaldehyde in a phosphate buffer for 30 minutes. After being rinsed, the organs were incubated overnight at 30"C in a X-gal solution. The whole organs were then frozen and treated appropriately so that cryosections (10 micrometers thick) could be prepared and these sections were stained with the aid of hematoxylin and eosin.
The demonstration by means of histochemical staining in the manner indicated above of beta-galactosidase activity in the sections prepared indicates the presence of the gene inserted into the adenovirus vector.
in the cells of the excised organs.
The macroscopic examination of the heart as well as the skeletal muscles excised from these treated mice reveals the great efficiency with which this gene transfer was made after only one injection of the recombinant adenovirus. The significance of the choice of the intravenous route resides in the fact that the viral vector is not concentrated in any particular zone of the muscle tissue but, conversely, it is favourably distributed throughout the muscle mass. The histochemical staining leads to estimates that the number of transformed cells in some zones attains as much as50% of the number of muscle cells present in this zone.
The expression of beta-galactosidase in the myocardium as well as in the skeletal muscles is perfectly stable. It was possible to observe positive stains 15, 33, 55, 66, 90, 127 and 150 days after the injection of the recombinant adenovirus. The expression of the gene seems to be constant as a function of time since the proportion of blue cells in the muscle tissues seem to be more or less the same from one month to the next.
The analysis of isolated muscle fibers reveals that a single fiber is likely to offer many "centers of expression".
Analyses by (Southern) immunoblot performed on the heart of a treated mouse have led to the demonstration of an intense and unique band at 35 kbp indicating that the viral DNA introduced into the muscle cells is essentially extrachromosomal.
Claims (13)
1. A method for delivering to human or animal muscle cells a non-replicative recombit-mt viral vector comprising a nucleic acid sequence encoding a polypeptide sequence, said method comprising the step of: injecting intravenously or intraarterially said recombinant vector, wherein said nucleic acid sequence is under the control of a promoter recognised by polymerases of said muscle cells and wherein said polypeptide is expressed in said muscle cells.
2. The method according to claim 1, wherein said recombinant vector is a defective adenovirus, the genome of which lacks essential sequences necessary for the replication of the adenovirus.
3. The method according to claim 2, wherein said defective adenovirus lacks the EA and EB transactivators. S.
4. The method according to claim 1, wherein the nucleic acid sequence is included in a defective adenovirus genome comprising all of the essential sequences necessary for the encapsidation of said adenovirus.
The method according to claim 1, wherein the nucleic acid sequence is constituted by all or part of a gene for dystrophin.
6. The method according to claim 5, for the treatment of Duchenne's muscular dystrophy.
7. The method according to claim 1, wherein the nucleic acid sequence codes for a protein or polypeptide having thrombolytic properties.
8. The method according to claim 7 for the treatment of cardiac diseases. 951 123,p:'oper\jrn,27902.92.clm,8 -9-
9. A recombinant vector comprising a defective genome of an adenovirus, comprising all of the essential sequences necessary for the encapsidation of said adenovirus, and in which is inserted a recombinant nucleic acid sequence wider the control of a promoter recognised by polymerases of human or animal muscle cells.
The recombinant vector according to claim 9, wherein said promoter is the strong promoter of the E1A early region of the genome of the adenovirus.
11. The recombinant vector according to claim 9, wherein the recombinant nucleic acid sequence is constituted by all or part of a gene for dystrophin.
12. The recombinant vector according to claim 9, wherein the recombinant nucleic acid sequence codes for a protein or polypeptide having thrombolytic properties.
13. A pharmaceutical composition comprising a recombinant vector according to any one of claims 9 to 12, in combination with a pharmaceutically acceptable vehicle. Dated this 23rd day of November, 1995 e i Centre National de la Recherche Scientifique By its Patent Attorneys 1: SDavies Collison Cave *S s s 951123,p.\opcr\jms,27902.92.cim9
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9111947 | 1991-09-27 | ||
| FR9111947A FR2681786A1 (en) | 1991-09-27 | 1991-09-27 | RECOMBINANT VECTORS OF VIRAL ORIGIN, PROCESS FOR OBTAINING SAME AND THEIR USE FOR THE EXPRESSION OF POLYPEPTIDES IN MUSCLE CELLS. |
| PCT/FR1992/000898 WO1993006223A1 (en) | 1991-09-27 | 1992-09-25 | Viral recombinant vectors for expression in muscle cells |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2790292A AU2790292A (en) | 1993-04-27 |
| AU666142B2 true AU666142B2 (en) | 1996-02-01 |
Family
ID=9417378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU27902/92A Expired AU666142B2 (en) | 1991-09-27 | 1992-09-25 | Viral recombinant vectors for expression in muscle cells |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0559884B2 (en) |
| JP (1) | JP3487597B2 (en) |
| AT (1) | ATE192500T1 (en) |
| AU (1) | AU666142B2 (en) |
| CA (1) | CA2097185C (en) |
| DE (1) | DE69230993T3 (en) |
| DK (1) | DK0559884T4 (en) |
| ES (1) | ES2147553T5 (en) |
| FR (1) | FR2681786A1 (en) |
| GR (1) | GR3034094T3 (en) |
| SG (1) | SG49081A1 (en) |
| WO (1) | WO1993006223A1 (en) |
Families Citing this family (79)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5538722A (en) * | 1989-06-13 | 1996-07-23 | Stanford University | Isolation, growth, differentiation and genetic engineering of human muscle cells |
| WO1994010322A1 (en) * | 1992-10-29 | 1994-05-11 | Board Of Regents, The University Of Texas System | Adenovirus-mediated ldl receptor gene transfer and targeting |
| WO1994011506A1 (en) * | 1992-11-18 | 1994-05-26 | Arch Development Corporation | Adenovirus-mediated gene transfer to cardiac and vascular smooth muscle |
| FR2705361B1 (en) * | 1993-05-18 | 1995-08-04 | Centre Nat Rech Scient | Viral vectors and use in gene therapy. |
| US6133028A (en) * | 1993-05-28 | 2000-10-17 | Transgene S.A. | Defective adenoviruses and corresponding complementation lines |
| FR2705686B1 (en) * | 1993-05-28 | 1995-08-18 | Transgene Sa | New defective adenoviruses and corresponding complementation lines. |
| US5919676A (en) * | 1993-06-24 | 1999-07-06 | Advec, Inc. | Adenoviral vector system comprising Cre-loxP recombination |
| US6730507B1 (en) | 1993-06-24 | 2004-05-04 | Merck & Co., Inc. | Use of helper-dependent adenoviral vectors of alternative serotypes permits repeat vector administration |
| US6080569A (en) * | 1993-06-24 | 2000-06-27 | Merck & Co., Inc. | Adenovirus vectors generated from helper viruses and helper-dependent vectors |
| US6140087A (en) * | 1993-06-24 | 2000-10-31 | Advec, Inc. | Adenovirus vectors for gene therapy |
| US6120764A (en) * | 1993-06-24 | 2000-09-19 | Advec, Inc. | Adenoviruses for control of gene expression |
| WO1995000655A1 (en) * | 1993-06-24 | 1995-01-05 | Mc Master University | Adenovirus vectors for gene therapy |
| US20020136708A1 (en) | 1993-06-24 | 2002-09-26 | Graham Frank L. | System for production of helper dependent adenovirus vectors based on use of endonucleases |
| US7045347B2 (en) | 1993-06-24 | 2006-05-16 | Advec, Inc. | Helper dependent adenovirus vectors based on integrase family site-specific recombinases |
| FR2718749B1 (en) * | 1994-04-18 | 1996-05-31 | Centre Nat Rech Scient | Viral vectors and use in gene therapy. |
| AU7264694A (en) * | 1993-07-13 | 1995-02-13 | Rhone-Poulenc Rorer S.A. | Defective adenovirus vectors and use thereof in gene therapy |
| FR2707664B1 (en) * | 1993-07-13 | 1995-09-29 | Centre Nat Rech Scient | Viral vectors and use in gene therapy. |
| FR2712812B1 (en) * | 1993-11-23 | 1996-02-09 | Centre Nat Rech Scient | Composition for the production of therapeutic products in vivo. |
| US6379943B1 (en) | 1999-03-05 | 2002-04-30 | Merck & Co., Inc. | High-efficiency Cre/loxp based system for construction of adenovirus vectors |
| US6465253B1 (en) | 1994-09-08 | 2002-10-15 | Genvec, Inc. | Vectors and methods for gene transfer to cells |
| US5846782A (en) | 1995-11-28 | 1998-12-08 | Genvec, Inc. | Targeting adenovirus with use of constrained peptide motifs |
| FR2730637B1 (en) | 1995-02-17 | 1997-03-28 | Rhone Poulenc Rorer Sa | PHARMACEUTICAL COMPOSITION CONTAINING NUCLEIC ACIDS, AND USES THEREOF |
| US5770442A (en) * | 1995-02-21 | 1998-06-23 | Cornell Research Foundation, Inc. | Chimeric adenoviral fiber protein and methods of using same |
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| AU576907B2 (en) * | 1984-11-01 | 1988-09-08 | American Home Products Corporation | Oral vaccines comprising live recombinant adenoviruses |
| AU612983B2 (en) * | 1986-08-01 | 1991-07-25 | Australian National University, The | Recombinant vaccine |
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| FR2573436B1 (en) * | 1984-11-20 | 1989-02-17 | Pasteur Institut | RECOMBINANT DNA COMPRISING A NUCLEOTIDE SEQUENCE ENCODING A DETERMINED POLYPEPTIDE UNDER THE CONTROL OF AN ADENOVIRUS PROMOTER, VECTORS CONTAINING THIS RECOMBINANT DNA, EUKARYOT CELLS TRANSFORMED BY THIS RECOMBINANT DNA, THE CONSTITUTION OF VACCINES |
| DE69034078T2 (en) * | 1989-03-21 | 2004-04-01 | Vical, Inc., San Diego | Expression of exogenous polynucleotide sequences in vertebrates |
| AU647391B2 (en) * | 1989-05-01 | 1994-03-24 | University Of Notre Dame Du Lac, The | Methods and materials for expression of human plasminogen in a eukaryotic cell system |
| GB9001766D0 (en) * | 1990-01-25 | 1990-03-28 | Univ Court Of The University O | Vaccines |
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1991
- 1991-09-27 FR FR9111947A patent/FR2681786A1/en active Granted
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1992
- 1992-09-25 DK DK92921684T patent/DK0559884T4/en active
- 1992-09-25 AU AU27902/92A patent/AU666142B2/en not_active Expired
- 1992-09-25 EP EP92921684A patent/EP0559884B2/en not_active Expired - Lifetime
- 1992-09-25 WO PCT/FR1992/000898 patent/WO1993006223A1/en not_active Ceased
- 1992-09-25 CA CA002097185A patent/CA2097185C/en not_active Expired - Lifetime
- 1992-09-25 DE DE69230993T patent/DE69230993T3/en not_active Expired - Lifetime
- 1992-09-25 SG SG1996005855A patent/SG49081A1/en unknown
- 1992-09-25 JP JP50585393A patent/JP3487597B2/en not_active Expired - Lifetime
- 1992-09-25 ES ES92921684T patent/ES2147553T5/en not_active Expired - Lifetime
- 1992-09-25 AT AT92921684T patent/ATE192500T1/en active
-
2000
- 2000-08-02 GR GR20000401791T patent/GR3034094T3/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU576907B2 (en) * | 1984-11-01 | 1988-09-08 | American Home Products Corporation | Oral vaccines comprising live recombinant adenoviruses |
| AU612983B2 (en) * | 1986-08-01 | 1991-07-25 | Australian National University, The | Recombinant vaccine |
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| Title |
|---|
| HUMAN GENE TRANSFER VOLUME 219 PP51-61 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE69230993T3 (en) | 2004-12-16 |
| ATE192500T1 (en) | 2000-05-15 |
| DK0559884T4 (en) | 2004-08-02 |
| JPH06502771A (en) | 1994-03-31 |
| EP0559884B1 (en) | 2000-05-03 |
| ES2147553T3 (en) | 2000-09-16 |
| DE69230993D1 (en) | 2000-06-08 |
| AU2790292A (en) | 1993-04-27 |
| CA2097185A1 (en) | 1993-03-28 |
| EP0559884B2 (en) | 2004-04-07 |
| DK0559884T3 (en) | 2000-10-02 |
| GR3034094T3 (en) | 2000-11-30 |
| CA2097185C (en) | 2007-07-24 |
| FR2681786B1 (en) | 1995-05-12 |
| SG49081A1 (en) | 1998-05-18 |
| WO1993006223A1 (en) | 1993-04-01 |
| EP0559884A1 (en) | 1993-09-15 |
| JP3487597B2 (en) | 2004-01-19 |
| ES2147553T5 (en) | 2004-11-16 |
| DE69230993T2 (en) | 2000-11-30 |
| FR2681786A1 (en) | 1993-04-02 |
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