WO1995016032A1 - Acide nucleique antisens pour le traitement de maladies dans lesquelles l'expression de bfgf, pdgf-a ou pdgf-b joue un role pathogene - Google Patents

Acide nucleique antisens pour le traitement de maladies dans lesquelles l'expression de bfgf, pdgf-a ou pdgf-b joue un role pathogene Download PDF

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Publication number
WO1995016032A1
WO1995016032A1 PCT/EP1993/003461 EP9303461W WO9516032A1 WO 1995016032 A1 WO1995016032 A1 WO 1995016032A1 EP 9303461 W EP9303461 W EP 9303461W WO 9516032 A1 WO9516032 A1 WO 9516032A1
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WO
WIPO (PCT)
Prior art keywords
pdgf
bfgf
nucleic acid
seq
dna
Prior art date
Application number
PCT/EP1993/003461
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English (en)
Inventor
Georg Ferdinand Schlingensiepen
Wolfgang Brysch
Reimar Schlingensiepen
Karl-Hermann Schlingensiepen
Original Assignee
Biognostik Gesellschaft für Biomolekulare Diagnostik mbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Biognostik Gesellschaft für Biomolekulare Diagnostik mbH filed Critical Biognostik Gesellschaft für Biomolekulare Diagnostik mbH
Priority to AU56980/94A priority Critical patent/AU5698094A/en
Priority to PCT/EP1993/003461 priority patent/WO1995016032A1/fr
Publication of WO1995016032A1 publication Critical patent/WO1995016032A1/fr

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Classifications

    • 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
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • 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
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • 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
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
    • 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
    • C12N15/1136—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 growth factors, growth regulators, cytokines, lymphokines or hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates

Definitions

  • the present invention is related to an antisense-nucleic acid or effective derivatives thereof hybridizing with an area of the messenger RNA (mRNA) or the DNA, encoding platelet derived growth factor-A (PDGF-A) or platelet derived growth factor-B (PDGF-B) or basic fibroblast growth factor (bFGF) , a pharmaceutical composition, comprising an antisense nucleic acid or effective derivatives thereof hybridizing with an area of the messenger RNA (mRNA) or the DNA, encoding PDGF-A or PDGF-B or bFGF as well as the use of said antisense nucleic acids and derivatives thereof for the manufacturing of a pharmacautieal composition for the treatment of neo ⁇ plasms, for the inhibtion of pathological angiogenesis or the treatment of rheumatoid arthritis and other autoimmune diseases .
  • mRNA messenger RNA
  • PDGF-A platelet derived growth factor-A
  • PDGF-B platelet
  • PDGF-A and PDGF-B as well as bFGF are growth factors, secreted by a variety of neoplastic cells including glioma cells, pancreas carcinoma cells, osteosarcoma cells, AIDS- related Kaposi's sarcoma cells, gastric carcinoma cells, lung carcinoma cells and melanoma cells and stimulate neoplastic cell growth in an autocrine manner. All three growth factors also stimulates neoangiogenesis in solid tumors. Furthermore, these factors may promote angiogenesis and pathological formation of tissue deposits in autoimmune diseases.
  • the antisense nucleic acids described below could strongly inhibit tumor cell growth, capillary endo- thelial cell growth and fibroblast cell growth even when the purified growth factors were added to the culture. This suggests that these growth factors exert growth regulatory effects by mechanisms independent of exogenous binding of these factors to their known receptors on the cell surface.
  • the intracellularly produced polypetides or fragments thereof may bind regulatory sites on the cellular DNA or to protein or to intra cellular receptor sites.
  • the oligonucleotides may act as aptamers.
  • antisense nucleic acids or effective derivatives thereof which hybridize with an area of the mRNA or DNA coding for PDGF-A or PDGF-B or bFGF can effectively treat the diseases addressed above.
  • the antisense nucleic acid is able to hybridize with regions of the PDGF-A or PDGF-B or bFGF mRNAs . It is understood by the skilled person that fragments of the antisense nucleic acids and antisense nucleic acids containing these sequences work according to the invention so long as production of the PDGF-A or PDGF-B or bFGF polypeptides is reduced or in ⁇ hibited.
  • the antisense-oligonucleotides are obtainable by solid phase synthesis using phosphite triester chemistry by growing the nucleotide chain in 3 '-5' direction in that the respective nucleotide is coupled to the first nucleotide which is covalently attached to the solid phase comprising the steps of cleaving 5'DMT protecting group of the previous nucleotide,
  • oligodeoxy-ribonucleotides are given in figure 1 as well as the respective structures of antisense oligo-ribonucleotides are given in figure 2.
  • the oligonucleotide chain is to be understood as a detail out of a longer nucleotide chain.
  • B means an organic base such as adenine (A) , guanine (G) , cytosine (C) and thymine (T) which are coupled via N9(A,G) or N1(D,T) to the desoxyribose.
  • A adenine
  • G guanine
  • C cytosine
  • T thymine
  • the sequence of the bases is the reverse complement of the genetic target sequence (mRNA-sequence) .
  • the modifications used are
  • B deoxy-ribonucleotide dA, dC, dG or dT depending on gene sequence
  • p internucleotide phosphate
  • n an oligodeoxy-ribonucleotide stretch of length 6 - 20 bases
  • B deoxy-ribonucleotide dA, dC, dG or dT depending on gene sequence
  • p internucleotide phosphate
  • n an oligodeoxy-ribodinucleotide stretch o. length 4 - 12 dinucleotides
  • RNA-oligonucleotides are the basis (adenine (A) , guanine (G) , cytosine (C) , uracil (U) ) coupled via N9 (A,G) or Nl (C,U) to the ribose.
  • the sequence of the basis is the reverse complement of the genetic target sequence (mRNA-sequence) .
  • the modifications in the oligo ⁇ nucleotide sequence used are as follows
  • B ribonucleotide A, C, G or T depending on gene sequence
  • p internucleotide phosphate
  • n an oligo-ribonucleotide stretch of length 4 20 bases
  • B ribonucleotide A, C, G or T depending on gene sequence
  • p internucleotide phosphate
  • n an oligo-ribodinucleotide stretch of length 4 - 12 dinucleotides
  • the PDGF-A antisense-oligo- nucleotide has the sequence as disclosed in the sequence listing under Seq. ID No. 1 - 6, having a DNA- or RNA-type structure.
  • the PDGF-B antisense-oligonuclotide has the sequence as disclosed in the sequence listing under Seq. ID No. 7 - 12, having a DNA- or RNA-type structure.
  • the bFGF'antisense-oligonucleotide has the sequence as disclosed in the sequence listing under Seq. ID No. 13 - 27, having a DNA- or RNA-type structure.
  • these oligonucleotides are phosphorothioate derivatives, having a DNA- or RNA-type structure.
  • one single individual sequence as mentioned above works as an antisense nucleic acid or oligo ⁇ nucleotide structure according to the invention.
  • one strand of nucleotides comprises more than one of the sequences as mentioned above directly covalently linked or with other nucleotides covalently linked in between.
  • individual oligonucleotides are addressed .
  • the randomized control sequence is disclosed in the sequence listing under Seq. ID No. 28.
  • these oligo-nucleotides are phosphorothioate derivatives.
  • the antisense-oligonucleotides are ad ⁇ vantageous since they are not as fast destroyed by endo- geneous factors when applied as this is valid for naturally occuring nucleotide sequences.
  • the modification is a phosphorothioate modification.
  • Oligodeoxy-nucleotides were synthesized by stepwise 5'- addition of protected nucleosides using phosphite triester chemistry.
  • the nucleotide A was introduced as 5'dimethoxy- trityl-deoxyadenosine (N-benzoyl) -N,N' -diisopropyl-2-cyano- ethyl phosphoramidite (0.1 M) ;
  • C was introduced by a 5'-
  • Synthesis was performed on controlled pore glass particles of approximately 150 ⁇ m diameter (pore diameter 500 A) to which the most 3' nucleoside is covalently attached via a long-chain alkylamin linker (average loading 30 ⁇ mol/g solid support ) .
  • the solid support was loaded into a cylindrical synthesis column, capped on both ends with filters which permit ade ⁇ quate flow of reagents but hold back the solid synthesis support. Reagents were delivered and withdrawn from the synthesis column using positive pressure of inert gas. The nucleotides were added to the growing oligonucleotide chain in 3'-> 5' direction. Each nucleotide was coupled using one round of the following synthesis cycle:
  • the anisense-nucleic acid of the invention can be used as pharmaceutical composition or medicament.
  • This medicament can be used for treating neoplasms in which the expression of platelet derived growth factor or basic fibroblast growth factor is of relevance for the pathogenicity. It can be used to reduce neoplastic cell growth in cells expressing these growth factors, and to inhibit pathological angiogenesis . Furthermore, it can be used to treat rheumatoid arthritis and other autoimmune diseases in which the production of PDGF-A, PDGF-B or bFGF is of pathogenetic relevance.
  • PDGF-A and PDGF-B and bFGF specific antisense oligonucleotides were investigated. It was demonstrated that antisense oligodeoxynucleotides as well as phosphorothioate modified nucleic acids, comple ⁇ mentary to PDGF and bFGF mRNAs could specifically inhibit PDGF protein expression and bFGF protein expression re ⁇ spectively. Furthermore, they reduced cell proliferation in mammary carcinoma, glioma, pancreas carcinoma and melanoma cells with surprising efficiency.
  • Cell lysates were diluted in 50 mM carbonate buffer at pH 9.0 and immobilized on immunon II plates (Dynatech Laborator ⁇ ies, Inc.) overnight. Antigen solution was removed and 200 ⁇ l/well phosphate buffered saline (PBS)/ l%/BSA/0.02% azide were added to block non-specific protein binding. Following incubation at room temperature for 2 h solution was removed. After washing with PBS plates were air dried for 3 h. Specific antibodies for PDGF-A, PDGF-B or bFGF (Oncogene or Santa Cruz Biotechnology Inc.) were added at 50 ⁇ l/well, diluted in blocking buffer.
  • PBS phosphate buffered saline
  • bFGF Oncogene or Santa Cruz Biotechnology Inc.
  • TITLE OF INVENTION Antisense nucleic acid for the treatment of neoplasms and auto-immune diseases and diseases involving pathological angioneogenesis, in which expression of the growth factors bFGF, PDGF-A or PDGF-B..
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES
  • MOLECULE TYPE DNA (genomic)
  • ANTI-SENSE YES

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)
  • Plant Pathology (AREA)
  • Microbiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé qui permet de prévenir et de traiter les maladies néoplastiques et/ou auto-immunes dans lesquelles l'expression de PDGF-A, PDGF-B et/ou bFGF joue un rôle pathogène.
PCT/EP1993/003461 1993-12-09 1993-12-09 Acide nucleique antisens pour le traitement de maladies dans lesquelles l'expression de bfgf, pdgf-a ou pdgf-b joue un role pathogene WO1995016032A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU56980/94A AU5698094A (en) 1993-12-09 1993-12-09 Antisense nucleic acid for the treatment of diseases in which expression of bfgf, pdgf-a or pdgf-b plays a pathogenic role
PCT/EP1993/003461 WO1995016032A1 (fr) 1993-12-09 1993-12-09 Acide nucleique antisens pour le traitement de maladies dans lesquelles l'expression de bfgf, pdgf-a ou pdgf-b joue un role pathogene

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1993/003461 WO1995016032A1 (fr) 1993-12-09 1993-12-09 Acide nucleique antisens pour le traitement de maladies dans lesquelles l'expression de bfgf, pdgf-a ou pdgf-b joue un role pathogene

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997044046A1 (fr) * 1996-05-17 1997-11-27 Otsuka Pharmaceutical Co., Ltd. Agent inhibiteur de l'expression du facteur de croissance d'origine plaquettaire
WO2005087269A1 (fr) * 2004-03-16 2005-09-22 Dnavec Research Inc. Procédé d'inhibition de la prolifération d'une tumeur
WO2005020972A3 (fr) * 2003-08-27 2005-11-17 Eyetech Pharmaceuticals Inc Polytherapie pour le traitement de troubles neovasculaires oculaires
WO2009033690A1 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Bfgf (119-126) pour des applications thérapeutiques
WO2009033687A1 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Spantide ii et bfgf (119-126) pour des applications thérapeutiques
US11273171B2 (en) 2013-07-12 2022-03-15 Iveric Bio, Inc. Methods for treating or preventing ophthalmological conditions

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992017206A1 (fr) * 1991-03-28 1992-10-15 The Victoria University Of Manchester Cicatrisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992017206A1 (fr) * 1991-03-28 1992-10-15 The Victoria University Of Manchester Cicatrisation

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BEHL, C. ET AL.: "Autocrine growth regulation in neuroectodermal tumors as detected with oligodeoxynucleotide antisense molecules", NEUROSURGERY, vol. 33, no. 4, October 1993 (1993-10-01), pages 679 - 684 *
BEHL, C. ET AL.: "Autoinduction of platelet derived growth factor (PDGF) A-chain mRNA expression in a human melanoma cell line and growth inhibitory effects of PDGF A-chain mRNA-specific antisense molecules", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 193, no. 2, 15 June 1993 (1993-06-15), DULUTH, MINNESOTA US, pages 744 - 751 *
BETSHOLZ, C. ET AL.: "cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumor cell lines", NATURE, vol. 320, 24 April 1986 (1986-04-24), LONDON GB, pages 695 - 699 *
ECKSTEIN, F.: "Phosphorothioate analogues of nucleotides - tools for the investigation of biochemical processes", ANGEWANDTE CHEMIE. INTERNATIONAL EDITION, vol. 22, no. 6, June 1983 (1983-06-01), WEINHEIM DE, pages 423 - 439 *
ERICKSON, R. & IZANT, J.:'Gene regulation: biology of antisense RNA and DNA'; 1992, RAVEN PRESS, Ltd., NEW YORK pages 317-328, *
ITOH, H. ET AL.: "Antisense oligonucleotides complementary to PDGF mRNA attenuate angiotensin II-induced vascular hypertrophy", HYPERTENSION, vol. 16, no. 3, September 1990 (1990-09-01), pages 325 - 326 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997044046A1 (fr) * 1996-05-17 1997-11-27 Otsuka Pharmaceutical Co., Ltd. Agent inhibiteur de l'expression du facteur de croissance d'origine plaquettaire
WO2005020972A3 (fr) * 2003-08-27 2005-11-17 Eyetech Pharmaceuticals Inc Polytherapie pour le traitement de troubles neovasculaires oculaires
US7759472B2 (en) 2003-08-27 2010-07-20 Ophthotech Corporation Combination therapy for the treatment of ocular neovascular disorders
EP2281885A1 (fr) * 2003-08-27 2011-02-09 Ophthotech Corporation Combination thérapeutique pour le traitement des troubles oculaires néovasculaires
US8187597B2 (en) 2003-08-27 2012-05-29 Ophthotech Corporation Combination therapy for the treatment of ocular neovascular disorders
US8206707B2 (en) 2003-08-27 2012-06-26 Ophthotech Corporation Combination therapy for the treatment of ocular neovascular disorders
US8685397B2 (en) 2003-08-27 2014-04-01 Ophthotech Corporation Combination therapy for the treatment of ocular neovascular disorders
WO2005087269A1 (fr) * 2004-03-16 2005-09-22 Dnavec Research Inc. Procédé d'inhibition de la prolifération d'une tumeur
WO2009033690A1 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Bfgf (119-126) pour des applications thérapeutiques
WO2009033687A1 (fr) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Spantide ii et bfgf (119-126) pour des applications thérapeutiques
US11273171B2 (en) 2013-07-12 2022-03-15 Iveric Bio, Inc. Methods for treating or preventing ophthalmological conditions
US12016875B2 (en) 2013-07-12 2024-06-25 Iveric Bio, Inc. Methods for treating or preventing ophthalmological conditions

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