WO1990014090A1 - Arn bicatenaire therapeutique court de structure definie - Google Patents

Arn bicatenaire therapeutique court de structure definie Download PDF

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Publication number
WO1990014090A1
WO1990014090A1 PCT/US1989/002172 US8902172W WO9014090A1 WO 1990014090 A1 WO1990014090 A1 WO 1990014090A1 US 8902172 W US8902172 W US 8902172W WO 9014090 A1 WO9014090 A1 WO 9014090A1
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WO
WIPO (PCT)
Prior art keywords
dsrna
human
therapeutically
short
therapy
Prior art date
Application number
PCT/US1989/002172
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English (en)
Inventor
David H. Gillespie
William A. Carter
Original Assignee
Hem Research, Inc.
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.)
Filing date
Publication date
Application filed by Hem Research, Inc. filed Critical Hem Research, Inc.
Priority to EP19890906635 priority Critical patent/EP0473576A4/en
Priority to PCT/US1989/002172 priority patent/WO1990014090A1/fr
Priority to JP1503637A priority patent/JPH04507083A/ja
Publication of WO1990014090A1 publication Critical patent/WO1990014090A1/fr
Priority to NO91914529A priority patent/NO914529L/no
Priority to DK911889A priority patent/DK188991D0/da

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention generally relates to therapeutic compositions of matter, methods for producing said compositions and methods for administering said compositions to living organisms, including human beings.
  • dsRNA long, double-stranded RNA
  • dsRNA poly(I) :poly(C) and poly(I):poly (C 12 ,U)
  • Ampligen® are anticancer and antiAIDS agents (1).
  • These dsRNAs induce interferon and activate a variety of cellular enzymes (2).
  • These dsRNAs are enzymatically synthesized as high molecular weight nucleic acid polymers (m>300), using ribonucleoside diphosphates as substrate and polynucleotide phosphorylase (PNPase) as enzyme. Ampligen was created because its parent compound, poly(I) :poly(C), was toxic (3). In the 1960's, Drs.
  • Such short dsRNAs having the proper nucleotide sequence will be therapeutic by virtue of their biological activity. It should be emphasized that the prior art teaches away from the present invention by teaching the need for long, biodegradable dsRNA in order to preserve biological activity without toxicity.
  • Short dsRNA of defined sequence cannot be synthesized by the PNPase method.
  • PNPase cannot synthesize a nucleic acid of defined sequence because it is a terminal transferase and not a template-copying enzyme.
  • the helical content of dsRNAs of the homopolymer:homopolymer type constantly changes due to the "slippage" reaction. Slippage means that the two strands of the dsRNA molecule mover relative to each other since there is no complementary nucleotide register to fix the position of two strands relative to each other.
  • the present invention produces means for synthesizing stable short dsRNA of defined sequence.
  • FIG. 1 is an illustration of two types of short dsRNA of defined sequence.
  • a dsRNA with terminal "locks” while in FIG. IB is shown a dsRNA with a central "hinge”.
  • the dsRNA in FIG. 1 also contain "internal registers", which are indicated by A-U base pairs.
  • FIG. 2 is an illustration of a method for preparing a short dsRNA of defined sequence having terminal locks and internal registers.
  • FIG. 3 is an illustration f a method for preparing short dsRNA of defined sequence having a central or near-central hinge.
  • FIG. 4 is an illustration of a method for preparing short dsRNA of defined sequence having both terminal locks and a central or near-central hinge.
  • Types of dsRNA Types of dsRNA.
  • the present compositions of matter and methods relative to their use generally depend on the several embodiments thereof on the chemical modifications of protein-inducing and/or enzyme-activating dsRNA complex to render said complex less toxic to a living animal cell.
  • the chemically modified complexes disclosed herein retain the biological activity of unmodified complexes while being less toxic by mechanisms which are presently mysterious.
  • the dsRNA complexes which are of concern in the present invention may be modified by shortening said dsRNA while at the same time fixing the two strands in space relative to one another.
  • Figure 1 depicts two types of dsRNA envisioned in this application. Type A dsRNA is termed "locked dsRNA".
  • Hinged dsRNA contains an internal self-complementary stretch which folds in a restricted way to align the remaining dsRNA nucleotides (see also Figures 3 and 4 for example of hinged dsRNA) .
  • locks are complementary nucleotide pairs different from homopolymer stretches in the dsRNA.
  • Said locks, hinges and internal registers are referred to as heteropolymer regions in this application.
  • At one extreme is a homopolymer with a single heteropolymer nucleotide pair to fix the dsRNA register while at the other extreme is a totally heteropolymeric short dsRNA.
  • Both locked and hinged dsRNAs may contain single stranded regions terminally or internally ( Figure 2).
  • Locked RNA molecules of defined length and defined sequence can be synthesized from plasmid DNA vectors having promoters of defined sequence placed near the sequence of interest.
  • the vectors, enzymes and substrates are available from a variety of commercial sources.
  • the locked dsRNA depicted as structure [7] of Figure 2 can be made as follows.
  • the two deoxyoligonucleotides depicted at the top of Figure 2 (structure [1]) can be synthesized by an oligonucleotide synthesizer.
  • Hinged RNA molecules of defined length and defined sequence can be synthesized from plasmid DNA vectors having promoters of defined sequence placed near the sequence of interest.
  • the hinged dsRNA depicted as structure [8] of Figure 3 can be made as follows: The two deoxyoligunucleotides depicted at the top of Figure 3 (structures!II ) can be synthesized by an oligunucleotide synthesizer, annealed to produce structure [2] and cloned into pGEM4 previously cut with Eco Rl and Sma 1 yielding structure [3] .
  • RNA structure [4] which can be self-annealed to produce the dsRNA shown as structure [5] .
  • This hinged dsRNA can be used as is or can be trimmed with RNase to produce the dsRNA shown as structure ([6]), Figure 3.
  • dsRNA molecules of defined length and sequence with both locks and hinges can be synthesized by a slight modification of this above procedure, using Hind II instead of Sma 1 and using slightly different deoxyoligonucleotides, as depicted in Figure 4.
  • oligonucleotides conisting of RNA polymerase promoters flanking inserts specifying the present invention can be synthesized, annealed and transcribed directly, without cloning into a vector.
  • short dsRNA can be chemically synthesized. The essence of this invention lies in the structure and properties of the dsRNAs themselves; this example is given to enable one with ordinary skill in the art to prepare short therapeutic dsRNAs of defined sequence.
  • dsRNA Determining Biological Activity of Short dsRNA of Defined Sequence.
  • the biological activity of dsRNA can be assessed in several experimental systems which are routine in the art.
  • the antiviral properties of dsRNA can be measured by challenging dsRNA-treated cells with vesicular stomatitis virus (VSV) and measuring reduction in virus yield as described by (5). Similar procedures have been reported which measure the inhibition of VSV and other viruses.
  • VSV vesicular stomatitis virus
  • the antitumor properties of dsRNA can be evaluated by exposing tumor cells in tissue culture to dsRNA and measuring reduction in growth rate as described by (6).
  • the antitumor properties of dsRNA can also be measured by injecting dsRNA into nude mice bearing tumors and measuring tumor growth rate (7).
  • dsRNA to enhance natural killer cell or macrophage killing activity
  • All of these procedures are routine in the art and are cited by way of enabling one with ordinary skill in the art to measure the biological activity of dsRNA synthesized as described in the preceding section. The citing of these procedures should not be construed as limiting; other procedures for measuring the biological activity of dsRNA exist and are also well known in the art. 4) Determining the Absence of Toxicity of dsRNA of Defined Sequence.
  • dsRNA The toxicity or lack of it of dsRNA can be determined by procedures which have long been routine for testing a variety of potential therapeutics and which have long been routine for testing a variety of potential therapeutics and which have been applied to dsRNA as well.
  • Suitable test animals such as mice, rats, rabbits, dogs, monkeys, etc. or humans can be injected periodically with various quantities of dsRNA and after a suitable interval, such animals can be examined for evidence of fever, loss of weight, loss of liver function, thrombocytopenia, leukopenia, bone marrow suppression, etc.
  • the examiner is directed particularly to Citations (9) for examples where such studies have been done regarding dsRNA.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'induction de protéines ainsi que l'activation d'enzymes dans les cellules d'organismes vivants, parmi lesquels l'homme. Selon l'invention on modifie des complexes d'acides nucléiques longs, tels que des complexes de polyriboinosinate et de polycytidylate, afin de produire un ARN bicaténaire court de séquence définie. Lesdits ARN bicaténaires courts de séquence définie conservent la capacité d'induire des protéines et d'activer des enzymes, mais ne sont pas aussi toxiques que les ARN bicaténaires longs.
PCT/US1989/002172 1989-05-19 1989-05-19 Arn bicatenaire therapeutique court de structure definie WO1990014090A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP19890906635 EP0473576A4 (en) 1989-05-19 1989-05-19 Short therapeutic dsrna of defined structure
PCT/US1989/002172 WO1990014090A1 (fr) 1989-05-19 1989-05-19 Arn bicatenaire therapeutique court de structure definie
JP1503637A JPH04507083A (ja) 1989-05-19 1989-05-19 規定された構造の短い治療用ｄｓＲＮＡ
NO91914529A NO914529L (no) 1989-05-19 1991-11-19 Kort terapeutisk dsrna med definert struktur
DK911889A DK188991D0 (da) 1989-05-19 1991-11-19 Terapeutisk virksom kort, dobbeltstrenget rna

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1989/002172 WO1990014090A1 (fr) 1989-05-19 1989-05-19 Arn bicatenaire therapeutique court de structure definie

Publications (1)

Publication Number Publication Date
WO1990014090A1 true WO1990014090A1 (fr) 1990-11-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1989/002172 WO1990014090A1 (fr) 1989-05-19 1989-05-19 Arn bicatenaire therapeutique court de structure definie

Country Status (5)

Country Link
EP (1) EP0473576A4 (fr)
JP (1) JPH04507083A (fr)
DK (1) DK188991D0 (fr)
NO (1) NO914529L (fr)
WO (1) WO1990014090A1 (fr)

Cited By (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012229A1 (fr) * 1991-12-18 1993-06-24 Cis Bio International Procede de preparation d'arn double-brin, et ses applications
WO2000001846A2 (fr) * 1998-07-03 2000-01-13 Devgen N.V. Caracterisation d'une fonction de gene par inhibition d'arn double brin
WO2000068374A1 (fr) * 1999-05-10 2000-11-16 Syngenta Participations Ag Regulation de l'expression d'un gene viral
WO2003070918A3 (fr) * 2002-02-20 2004-07-08 Ribozyme Pharm Inc Inhibition mediee par interference arn d'une expression genique faisant appel a des acides nucleiques interferants courts chimiquement modifies (sina)
GB2397818A (en) * 2002-02-20 2004-08-04 Sirna Therapeutics Inc Rna interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid
NL1026335C2 (nl) * 2004-06-04 2005-12-06 Univ Delft Tech Werkwijze voor het maken van een dubbelstrengs polyribonucleotidenvolgorde met overhangend uiteinde, alsmede een werkwijze voor het vormen van een dubbelstrengs polynucleotidenconstruct en een toepassing.
US7005423B1 (en) 1999-07-02 2006-02-28 Devgen Nv Characterization of gene function using double stranded RNA inhibition
US7022828B2 (en) 2001-04-05 2006-04-04 Sirna Theraputics, Inc. siRNA treatment of diseases or conditions related to levels of IKK-gamma
US7176304B2 (en) 2002-02-20 2007-02-13 Mcswiggen James RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA)
US7491805B2 (en) 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
US7560438B2 (en) 1997-12-23 2009-07-14 The Carnegie Institution Of Washington Genetic inhibition by double-stranded RNA
US7659390B2 (en) 2002-02-20 2010-02-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of muscarinic colinergic receptor gene expression using short interfering nucleic acid (siNA)
US7659389B2 (en) 2001-05-18 2010-02-09 Sirna Therapeutics, Inc. RNA interference mediated inhibition of MYC and/or MYB gene expression using short interfering nucleic acid (siNA)
US7662952B2 (en) 2002-02-20 2010-02-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of GRB2 associated binding protein (GAB2) gene expression using short interfering nucleic acid (siNA)
US7662951B2 (en) 2000-08-30 2010-02-16 Sirna Therapeutics, Inc. RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA)
US7667029B2 (en) 2002-02-20 2010-02-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of checkpoint kinase-1 (CHK-1) gene expression using short interfering nucleic acid (siNA)
US7667030B2 (en) 2002-02-20 2010-02-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of matrix metalloproteinase 13 (MMP13) gene expression using short interfering nucleic acid (siNA)
US7678897B2 (en) 2002-02-20 2010-03-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of platelet-derived endothelial cell growth factor (ECGF1) gene expression using short interfering nucleic acid (siNA)
US7691999B2 (en) 2002-02-20 2010-04-06 Sirna Therapeutics, Inc. RNA interference mediated inhibition of NOGO and NOGO receptor gene expression using short interfering nucleic acid (siNA)
US7700760B2 (en) 2002-02-20 2010-04-20 Sirna Therapeutics, Inc. RNA interference mediated inhibition of vascular cell adhesion molecule (VCAM) gene expression using short interfering nucleic acid (siNA)
US7744900B2 (en) 1999-04-08 2010-06-29 Novartis Vaccines And Diagnostics, Inc. Enhancement of the immune response for vaccine and gene therapy applications
US7795422B2 (en) 2002-02-20 2010-09-14 Sirna Therapeutics, Inc. RNA interference mediated inhibition of hypoxia inducible factor 1 (HIF1) gene expression using short interfering nucleic acid (siNA)
US7833992B2 (en) 2001-05-18 2010-11-16 Merck Sharpe & Dohme Conjugates and compositions for cellular delivery
US7858625B2 (en) 2001-05-18 2010-12-28 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
US7858769B2 (en) 2004-02-10 2010-12-28 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using multifunctional short interfering nucleic acid (multifunctional siNA)
US7888325B2 (en) 1999-01-28 2011-02-15 Medical College Of Georgia Research Institute, Inc. Composition and method for in vivo and in vitro attenuation of gene expression using double stranded RNA
US7893248B2 (en) 2002-02-20 2011-02-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of Myc and/or Myb gene expression using short interfering nucleic acid (siNA)
US7897752B2 (en) 2002-02-20 2011-03-01 Sirna Therapeutics, Inc. RNA interference mediated inhibition of telomerase gene expression using short interfering nucleic acid (siNA)
US7897757B2 (en) 2002-02-20 2011-03-01 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA)
US7897753B2 (en) 2002-02-20 2011-03-01 Sirna Therapeutics, Inc. RNA interference mediated inhibition of XIAP gene expression using short interfering nucleic acid (siNA)
US7910725B2 (en) 2002-02-20 2011-03-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (siNA)
US7910724B2 (en) 2002-02-20 2011-03-22 Sirna Therapeutics, Inc. RNA interference mediated inhibition of Fos gene expression using short interfering nucleic acid (siNA)
US7915400B2 (en) 2002-02-20 2011-03-29 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of hepatitis C virus (HCV) gene expression using short interfering nucleic acid (siNA)
US7923549B2 (en) 2002-02-20 2011-04-12 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (siNA)
US7923547B2 (en) 2002-09-05 2011-04-12 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US7928218B2 (en) 2002-02-20 2011-04-19 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of polycomb group protein EZH2 gene expression using short interfering nucleic acid (siNA)
US7928219B2 (en) 2002-02-20 2011-04-19 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (SINA)
US7928220B2 (en) 2002-02-20 2011-04-19 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of stromal cell-derived factor-1 (SDF-1) gene expression using short interfering nucleic acid (siNA)
US7935812B2 (en) 2002-02-20 2011-05-03 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of hepatitis C virus (HCV) expression using short interfering nucleic acid (siNA)
US7943757B2 (en) 2002-02-20 2011-05-17 Mcswiggen James RNA interference mediated inhibition of intercellular adhesion molecule (ICAM) gene expression using short interfering nucleic acid (siNA)
US7977472B2 (en) 2002-02-20 2011-07-12 Leonid Beigelman RNA interference mediated inhibition of myostatin gene expression using short interfering nucleic acid (siNA)
US7985853B2 (en) 2002-02-20 2011-07-26 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of platelet derived growth factor (PDGF) and platelet derived growth factor receptor (PDGFR) gene expression using short interfering nucleic acid (siNA)
US7989612B2 (en) 2002-02-20 2011-08-02 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US8008472B2 (en) 2001-05-29 2011-08-30 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of human immunodeficiency virus (HIV) gene expression using short interfering nucleic acid (siNA)
US8008473B2 (en) 2002-02-20 2011-08-30 Mcswiggen James RNA interference mediated inhibition of TNF and TNF receptor gene expression using short interfering nucleic acid (siNA)
US8013143B2 (en) 2002-02-20 2011-09-06 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of CXCR4 gene expression using short interfering nucleic acid (siNA)
US8017761B2 (en) 2001-05-18 2011-09-13 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of Stearoyl-CoA desaturase (SCD) gene expression using short interfering nucelic acid (siNA)
US8053419B2 (en) 1998-03-20 2011-11-08 Commonwealth Scientific And Industrial Research Organisation Synthetic genes and genetic constructs
US8067575B2 (en) 2002-02-20 2011-11-29 Merck, Sharp & Dohme Corp. RNA interference mediated inhibition of cyclin D1 gene expression using short interfering nucleic acid (siNA)
US8148604B2 (en) 2004-10-21 2012-04-03 Venganza Inc. Methods and materials for conferring resistance to pests and pathogens of plants
US8168774B2 (en) 1998-03-20 2012-05-01 Commonwealth Scientific And Industrial Research Organisation Control of gene expression
US8183217B2 (en) 1999-08-13 2012-05-22 Commonwealth Scientific And Industrial Research Organisation Methods and means for obtaining modified phenotypes
US8258288B2 (en) 2002-02-20 2012-09-04 Sirna Therapeutics, Inc. RNA interference mediated inhibition of respiratory syncytial virus (RSV) expression using short interfering nucleic acid (siNA)
US8273866B2 (en) 2002-02-20 2012-09-25 Merck Sharp & Dohme Corp. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SINA)
US8329890B2 (en) 2002-08-05 2012-12-11 University Of Iowa Research Foundation SiRNA-mediated gene silencing
US8481710B2 (en) 2002-08-05 2013-07-09 University Of Iowa Research Foundation RNA interference suppression of neurodegenerative diseases and methods of use thereof
US8524879B2 (en) 2002-08-05 2013-09-03 University Of Iowa Research Foundation RNA interference suppresion of neurodegenerative diseases and methods of use thereof
US8598332B1 (en) 1998-04-08 2013-12-03 Bayer Cropscience N.V. Methods and means for obtaining modified phenotypes
US9051566B2 (en) 2001-01-31 2015-06-09 Alnylam Pharmaceuticals, Inc. Post-transcriptional gene silencing using expressed double stranded RNA
US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9260471B2 (en) 2010-10-29 2016-02-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)
US9441239B2 (en) 1998-04-08 2016-09-13 Commonwealth Scientific & Industrial Research Organisation Methods and means for obtaining modified phenotypes
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9994853B2 (en) 2001-05-18 2018-06-12 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
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NO914529L (no) 1992-04-14
DK188991D0 (da) 1991-11-19
NO914529D0 (no) 1991-11-19
JPH04507083A (ja) 1992-12-10
EP0473576A4 (en) 1993-03-10
EP0473576A1 (fr) 1992-03-11

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