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WO1993009788A1 - Reactifs oligonucleotides constituant des triplex cibles sur le promoteur de l'oncogene neu et procede d'utilisation - Google Patents

Reactifs oligonucleotides constituant des triplex cibles sur le promoteur de l'oncogene neu et procede d'utilisation Download PDF

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Publication number
WO1993009788A1
WO1993009788A1 PCT/US1992/009202 US9209202W WO9309788A1 WO 1993009788 A1 WO1993009788 A1 WO 1993009788A1 US 9209202 W US9209202 W US 9209202W WO 9309788 A1 WO9309788 A1 WO 9309788A1
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Prior art keywords
cap
seq
tfo
oligonucleotide
group
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Inventor
Michael Edward Hogan
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Baylor College of Medicine
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Baylor College of Medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/15—Nucleic acids forming more than 2 strands, e.g. TFOs

Definitions

  • the present invention relates generally to a method of inhibiting the growth of cells using triplex forming oligonucleotides. More particularly it relates to the inhibition of cell growth using oligonucleotides which form triplexes to the promoter region of the erb
  • the c-erb B2/neu (HER-2) gene is the human homologue of the rat neu gene. Neu was originally identified in the rat in ethylnitrosourea transformed neuroblastomas. Subsequently, it has been shown that the
  • mice Amplification of c-erb B2/neu has been strongly correlated with poor patient prognosis.
  • the core promoter element of erb B2/neu resides within a 300 BP ⁇ * region of the 5' flanking domain. This region contains promoter- enhancer elements which confer sensitivity to enhanced promoter function ' * 25 in the presence of cell growth factors such as TPA, c-AMP and retinoic acid. Based upon those data, it can be argued that over expression of erb
  • B2/neu may be one mechanism leading to cancer initiation or progression.
  • the present invention provides a series of novel oligonucleotides targeted to the erb B2fneu gene and a novel method for treating proliferative growth of cells containing the erb B2fneu gene. These oligonucleotides and method can be used to treat cancer which results from abnormalities in the regulation of the erb B2/neu gene and in other non-malignant diseases such as psoriasis and scarring.
  • An object of the present invention is a method for inhibiting proliferating cells with triplex forming oligonucleotides specific to the promoter region of the erb B2/neu gene site.
  • a further object of the present invention is a method of treating cancer.
  • An additional object of the present invention is the provision of triplex forming oligonucleotides which are anti-cancer agents.
  • a method for inhibiting the proliferation of cells containing an erb B2/neu gene site comprising the step of administering a therapeutic dose of an oligonucleotide, said oligonucleotide capable of binding to the major groove of a duplex DNA to form a colinear triplex with the promoter region of the erb B2/neu gene.
  • the oligonucleotides can bind in the promoter region to the CAT box, the TATA box or the linking domain connecting the CAT box and TATA box.
  • the oligonucleotides are capped at the 3' terminus with a polyamine, a cholesterol or a poly-L-lysine modifier.
  • oligonucleotide as used herein is defined as a molecule comprised of two or more deoxyribonucleotides or ribonucleotides, preferably more than ten. Its exact size will depend on many factors including the specificity and binding affinity.
  • bases when referring to “bases” herein the term includes both deoxyribonucleic acids and ribonucleic acids.
  • A refers to adenine as well as its deoxyribose derivatives
  • T refers to thymine as well as its deoxyribose derivatives
  • G refers to guanine as well as its deoxyribose derivatives
  • C refers to cytosine as well as its deoxyribose derivatives.
  • the “major groove” refers to one of the grooves along the outer surface of the DNA helix which is formed because the sugar-phosphate backbone extends further from the axis than the bases.
  • the major groove is important for the binding of regulatory molecules to specific DNA sequences.
  • trim forming oligonucleotide or "TFO” is used herein to refer to the oligonucleotides of the present invention which are capable of forming a triplex by binding to the major groove of a duplex DNA structure.
  • inhibitory dose or “therapeutic dose” of the compounds in the present invention may be determined by assessing the effects of the oligonucleotide on cell growth in tissue culture or tissue growth in an animal.
  • the amount of oligonucleotide administered in a therapeutic dose is dependent upon the age, weight, kind of concurrent treatment and nature of the cell growth condition being treated.
  • the amount of oligonucleotide in a therapeutic dose will include a sufficient amount to account for cellular uptake and binding to the promoter site in the erb B2/neu gene.
  • One embodiment of the present invention is a method for inhibiting the proliferation of cells containing an erb B2/neu gene site, comprising the step of administering a therapeutic dose of a oligonucleotide.
  • the oligonucleotide is capable of binding to the major groove of a DNA triplex to form a colinear triplex with promoter region of the erb B2/neu gene.
  • duplex DNA of the promoter region of the erb B2/neu gene is shown in SE . ID. NO. 1. This strand is the purine rich strand.
  • the target site on the duplex DNA should have a stretch of DNA which is at least 65% purine or pyrimidine bases.
  • the TFO which is selected to bond to this region should be at least 20 nucleotides long.
  • the TFO is complementary to the identified target sequence.
  • the TFO includes a G when the complementary location in the duplex DNA is a GC base pair and T when the complementary location in the duplex DNA is an AT base pair.
  • the sequence can be either oriented 3' to 5' and bind anti-parallel to the at least 65% purine strand of the duplex DNA target sequence or be oriented 5' to 3' and bind parallel to the at least 65% purine strand of the duplex DNA target.
  • oligonucleotides will usually be inferior to the oligonucleotides having the G/GC and a T/AT relationship.
  • alterations to the bases, end capping and altered backbone structure will also affect triplex formation.
  • the erb B2/neu gene is a useful target because of its role in cancer and because its core promoter region SEQ. ID. NO. 1 possesses a long polypurine run. This long polypurine run serves as the linkage between the CAT box and the TATA box. In physical terms the polypurine rich sequences form the best target site for TFO's. Therefore, the promoter region of erb B2/neu provides an example of direct overlap between sites of transcriptional importance and an excellent, high infinity, selective TFO binding site.
  • Inhibition of protein binding at the CAT box transcription factor binding site will inhibit transcription initiation by interfering directly with the CAT box protein-RNA polymerase interaction. Further, inhibition of the protein binding at CAT box site can also block the interaction of the CAT protein with TFIId at the TATA box binding site.
  • TATA box binding domain TATA box binding domain
  • the erb B2fneu gene can be regulated by either TFO binding to the CAT box, TATA box or linker domain. Additionally, TFO's which overlap these domains can be synthesized. Thus a TFO can bind to a combination of sites within this promoter region to effectuate regulation and inhibition of the erb B2fneu gene.
  • sequences which can intervene with the proliferation of cells containing the erb B2fneu gene site are the anti-parallel sequences shown in SEQ. ID. NO. 2, SEQ. ID. NO. 3 and SEQ. ID. NO. 4 and the parallel sequences shown in SEQ. ID. NO. 5, SEQ. ID. NO. 6 and SEQ. ID. NO. 7.
  • SEQ. ID. NOS. 2 and 5 are 54 base pair length oligonucleotides which are capable of CAT box, TATA box and linker mediated inhibition of the promoter region.
  • SEQ. ID. NOS. 3 and 6 are the anti-parallel sequences shown in SEQ. ID. NO. 2, SEQ. ID. NO. 3 and SEQ. ID. NO. 4 and the parallel sequences shown in SEQ. ID. NO. 5, SEQ. ID. NO. 6 and SEQ. ID. NO. 7.
  • SEQ. ID. NOS. 2 and 5 are 54 base pair length oligonucleotides which are capable of CAT box
  • SEQ. ID. NOS. 4 and 7 are 28 base pair length oligonucleotides which are capable of CAT box and linker mediated inhibition.
  • the inhibition of the promoter region can be further enhanced by using 3' or 5' modifications, substitution with inosine, xanthine or other nucleotides or internal base modifications or by altering the backbone.
  • the sequences shown in SEQ. ID. Nos. 2-7 show excellent binding properties and selectivity and are thus excellent for inhibiting the expression of the erb B2fneu gene.
  • SEQ. ID. Nos.2-7 have a 3' terminus modification.
  • the capping of the 3' terminus with the modifier reduces the oligonucleotide's sensitivity to 3' exonucleases, thus increasing its biological half-life.
  • the a ine modifier can be selected from the group consisting of polyamine, poly-L-lysine and cholesterol.
  • propylamine is the 3' cap.
  • these oligonucleotides are useful in the treatment of cancers.
  • cancers which can respond to treatment are neuroblastoma, glioblastoma, breast adenocarcinoma and other tumors related to erb B2/neu gene expression.
  • the TFOs which selectively inhibit the erb B2/neu promoter region can be used to slow the growth of transformed cells and in certain instances reverse the transformation process.
  • the erb B2/neu gene function in normal cells in not completely understood, its protein product is a kinase. This protein kinase is very similar to the epidermal growth factor receptor and probably serves a related function.
  • the anti-new TFOs can also be useful as inhibitors of untransformed cell growth. Examples of cell growth which can be regulated include scarring and lesions such as psoriasis.
  • the disassociation constants (Kdiss) for SEQ. ID. Nos. 2-4 were measured by band shift analysis. Each TFO was added to the promoter binding site (SEQ. ID. NO. 1) as a duplex with its Watson/Crick complement. The conditions were 10 mM Tris/HCl at pH 7.8 and 10 ⁇ M Mg Cl,.
  • EXAMPLE 2 In Vivo Assay The cellular assay for ERB-B2fneu described by Hudson, Ertl and GiH, Journal of Biological Chemistry 265:4389-4393 (1990) was used. The control region of the ERB-B2 gene was Hnked to the luciferase tester gene.
  • the resulting gene chimera was expressed in HeLa ceUs and was under ordinary control of the ERB- B2fneu promoter.
  • the example described was performed on an ERB-B2// ⁇ eu luciferase chimera provided by G. N. Gill.
  • the cellular experiments described in the reference were repeated in HeLa cells with the addition of NEU-specific TFOs and controls. NEU-specific TFOs and controls were added to the cell culture medium at 5 micromolar concentrations. In this analysis, the
  • 3' propylamine derivatives were used to inhibit cellular nuclease activity. 10,000 cells were incubated for four hours with the ERB-B2/ ⁇ ew specific TFO or with a scrambled sequence isomer as a control. The gene activity was then monitored by measuring the amount of luciferase protein which remained in the cells after the four hour incubation period.
  • the randomized (scrambled) isomers do not bind to the target sequence in the NEU-B2 promoter region and do not show any binding or any inhibition activity of ERB-B2 promoter activity.
  • the target sequence for the TFOs of the present invention are shown in seq. Id. No. 1.
  • SEQ. ID. Nos. 3 and 4 the NEUctr sequence and Control 1 and Control 2 are shown below.
  • TFOs are capable of: (i) entering the ceH and the nucleus; (2) of binding duplex DNA targets; and (3) of inhibiting the function of the target.
  • the claimed TFOs are capable of in vivo inhibition of the promoter region of the ERB-B2/nezz gene.
  • MOLECULE TYPE DNA (genomic)
  • MOLECULE TYPE Triplex forming oligonucleotide
  • MOLECULE TYPE Triplex forming oligonucleotide
  • MOLECULE TYPE Triplex forming oligonucleotide
  • MOLECULE TYPE Triplex forming oligonucleotide
  • MOLECULE TYPE Triplex forming oligonucleotide
  • MOLECULE TYPE Triplex forming oligonucleotide
  • MOLECULE TYPE Triplex forming oligonucleotide
  • MOLECULE TYPE Triplex forming oligonucleotide
  • MOLECULE TYPE Triplex forming oligonucleotide

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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Physics & Mathematics (AREA)
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Abstract

Procédé servant à inhiber la prolifération de cellules contenant un site de gènes erb B2/neu. Le procédé implique l'administration d'une dose thérapeutique d'un oligonucléotide pouvant constituer un triplex colinéaire avec la région promotrice du gène erb B2/neu. Les oligonucléotides peuvent inhiber la boîte CAT, la boîte TATA ou le domaine de linkage situé entre la boîte CAT et la boîte TATA ou bien toute combinaison des trois. L'invention décrit les oligonucléotides spécifiques qui se fixeront et constitueront des triplex dans cette région.
PCT/US1992/009202 1991-11-13 1992-10-28 Reactifs oligonucleotides constituant des triplex cibles sur le promoteur de l'oncogene neu et procede d'utilisation Ceased WO1993009788A1 (fr)

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US79231991A 1991-11-13 1991-11-13
US07/792,319 1991-11-13

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995017507A1 (fr) * 1993-12-23 1995-06-29 Biognostik Gesellschaft für Biomolekulare Diagnostik mbH ACIDES NUCLEIQUES ANTI-SENS DESTINES A LA PREVENTION ET AU TRAITEMENT DE TROUBLES DANS LESQUELS INTERVIENT L'EXPRESSION DE c-erbB
WO1995023162A1 (fr) 1994-02-28 1995-08-31 Microprobe Corporation Duplex d'oligonucleotides modifies a activite anticancereuse
US5523389A (en) * 1992-09-29 1996-06-04 Isis Pharmaceuticals, Inc. Inhibitors of human immunodeficiency virus
US5955059A (en) * 1995-06-06 1999-09-21 Trustees Of Boston University Use of locally applied DNA fragments
US5968748A (en) * 1998-03-26 1999-10-19 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of human HER-2 expression
US6147056A (en) * 1995-06-06 2000-11-14 Trustees Of Boston University Use of locally applied DNA fragments
EP1275398A4 (fr) * 2000-04-06 2004-09-01 Kyowa Hakko Kogyo Kk Diagnostics et remedes contre la polyarthrite rhumatoide
US7033829B2 (en) 2000-03-31 2006-04-25 Trustees Of Boston University Method to inhibit cell growth using oligonucleotides
US7094766B1 (en) 1995-06-06 2006-08-22 Trustees Of Boston University Use of locally applied DNA fragments
US8183222B2 (en) 1995-06-06 2012-05-22 Trustees Of Boston University Method to inhibit cell growth using oligonucleotides
US8367628B2 (en) 2005-12-01 2013-02-05 Pronai Therapeutics, Inc. Amphoteric liposome formulation
US8815599B2 (en) 2004-06-01 2014-08-26 Pronai Therapeutics, Inc. Methods and compositions for the inhibition of gene expression
US9587238B1 (en) 2013-07-19 2017-03-07 Yale University Gene-targeted apoptosis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MOLECULAR AND CELLULAR BIOLOGY, Volume 7, No. 7, issued July 1987, M. TAL et al., "Human HER2 (neu) Promoter: Evidence for Multiple Mechanisms for Transcriptional Initiation", pages 2597-2601. *
SCIENCE, Volume 241, issued 22 July 1988, M. COONEY et al., "Site-Specific Oligonucleotide Binding Represses Transcription of the Human c-myc Gene In Vitro", pages 456-459. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5523389A (en) * 1992-09-29 1996-06-04 Isis Pharmaceuticals, Inc. Inhibitors of human immunodeficiency virus
US6365345B1 (en) 1993-12-23 2002-04-02 Biognostik Gesellscahft Für Biomokekulare Diagnostik mbH Antisense nucleic acids for the prevention and treatment of disorders in which expression of c-erbB plays a role
WO1995017507A1 (fr) * 1993-12-23 1995-06-29 Biognostik Gesellschaft für Biomolekulare Diagnostik mbH ACIDES NUCLEIQUES ANTI-SENS DESTINES A LA PREVENTION ET AU TRAITEMENT DE TROUBLES DANS LESQUELS INTERVIENT L'EXPRESSION DE c-erbB
WO1995023162A1 (fr) 1994-02-28 1995-08-31 Microprobe Corporation Duplex d'oligonucleotides modifies a activite anticancereuse
US5955059A (en) * 1995-06-06 1999-09-21 Trustees Of Boston University Use of locally applied DNA fragments
US6147056A (en) * 1995-06-06 2000-11-14 Trustees Of Boston University Use of locally applied DNA fragments
US7094766B1 (en) 1995-06-06 2006-08-22 Trustees Of Boston University Use of locally applied DNA fragments
US8183222B2 (en) 1995-06-06 2012-05-22 Trustees Of Boston University Method to inhibit cell growth using oligonucleotides
US5968748A (en) * 1998-03-26 1999-10-19 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of human HER-2 expression
US7033829B2 (en) 2000-03-31 2006-04-25 Trustees Of Boston University Method to inhibit cell growth using oligonucleotides
EP1275398A4 (fr) * 2000-04-06 2004-09-01 Kyowa Hakko Kogyo Kk Diagnostics et remedes contre la polyarthrite rhumatoide
US8815599B2 (en) 2004-06-01 2014-08-26 Pronai Therapeutics, Inc. Methods and compositions for the inhibition of gene expression
US9393258B2 (en) 2004-06-01 2016-07-19 Pronai Therapeutics, Inc. Methods and compositions for the inhibition of gene expression
US8367628B2 (en) 2005-12-01 2013-02-05 Pronai Therapeutics, Inc. Amphoteric liposome formulation
US9587238B1 (en) 2013-07-19 2017-03-07 Yale University Gene-targeted apoptosis

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