CA2677176A1 - Inhibition of bcl-2 protein expression by liposomal antisense oligodeoxynucleotides - Google Patents

Inhibition of bcl-2 protein expression by liposomal antisense oligodeoxynucleotides Download PDF

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Publication number
CA2677176A1
CA2677176A1 CA002677176A CA2677176A CA2677176A1 CA 2677176 A1 CA2677176 A1 CA 2677176A1 CA 002677176 A CA002677176 A CA 002677176A CA 2677176 A CA2677176 A CA 2677176A CA 2677176 A1 CA2677176 A1 CA 2677176A1
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CA
Canada
Prior art keywords
composition
polynucleotide
lipid
oligonucleotide
bcl
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Legal status (The legal status 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 status listed.)
Granted
Application number
CA002677176A
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French (fr)
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CA2677176C (en
Inventor
Mar Tormo
Ana M. Tari
Gabriel Lopez-Berestein
Timothy J. Mcdonnel
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University of Texas System
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Board Of Regents, The University Of Texas System
Mar Tormo
Ana M. Tari
Gabriel Lopez-Berestein
Timothy J. Mcdonnel
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Application filed by Board Of Regents, The University Of Texas System, Mar Tormo, Ana M. Tari, Gabriel Lopez-Berestein, Timothy J. Mcdonnel filed Critical Board Of Regents, The University Of Texas System
Publication of CA2677176A1 publication Critical patent/CA2677176A1/en
Application granted granted Critical
Publication of CA2677176C publication Critical patent/CA2677176C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • 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
    • C12N2310/312—Phosphonates
    • 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
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification

Abstract

The present invention provides novel compositions and methods for use in the treatment of Bcl-2-associated diseases like cancer, specifically, in the treatment of follicular lymphoma (FL). The compositions contain antisense oligonucleotides that hybridize to Bcl-2 nucleic acids, the gene products of which are known to interact with the tumorigenic protein Bcl-2.
Used alone, or in conjunction with other antisense oligonucleotides, these compositions inhibit the proliferation of FL cancer cells.

Claims (60)

1. A composition comprising:

a) a first polynucleotide that hybridizes to a second Bcl-2 encoding polynucleotide under intracellular conditions, wherein the first polynucleotide comprises at least 8 nucleotides; and b) a lipid component, wherein the lipid component is neutral in net charge.
2. The composition of claim 1, wherein the first polynucleotide is an oligonucleotide having a length of between about 8 and about 50 nucleotides.
3. The composition of claim 1, wherein the first polynucleotide is complementary to the translation initiation site of a Bcl-2 mRNA.
4. The composition of claim 3, wherein the polynucleotide is an oligonucleotide comprising the sequence CAGCGTGCGCCATCCTTC (SEQ ID
NO:1).
5. The composition of claim 1, wherein the lipid component is comprised in a liposome.
6. The composition of claim 5, wherein the first polynucleotide is incorporated in the liposome.
7. The composition of claim 1, wherein the lipid component comprises a phosphatidylcholine, a phosphatidylglycerol, or a phosphatidylethanolamine.
8. The composition of claim 7, wherein the lipid component comprises dioleoylphosphatidylcholine.
9. The composition of claim 1, wherein the first polynucleotide is further defined as a p-ethoxy oligonucleotide.
10. The composition of claim 1, wherein the first polynucleotide comprises a C-5 propyne pyrimidine.
11. The composition of claim 1, wherein the C-5 propyne pyrimidine is a C-propyne analogue of uridine.
12. The composition of claim 1, wherein the C-5 propyne pyrmidine is a C-5 propyne analogue of cytidine.
13. The composition of claim 1, wherein the first polynucleotide is further defined as a methyl phosphonate oligonucleotide.
14. The composition of claim 1, wherein the composition further comprises a surfactant.
15. A composition comprising a p-ethoxy oligonucleotide that hybridizes to a Bcl-2 encoding polynucleotide under intracellular conditions and a lipid associated with the p-ethoxy oligonucleotide, wherein the p-ethoxy oligonucleotide comprises at least 8 nucleotides.
16. The composition of claim 15, wherein the p-ethoxy oligonucleotide is an oligonucleotide having a length of between about 8 and about 50 nucleotides.
17. The composition of claim 15, wherein the p-ethoxy oligonucleotide is complementary to the translation initiation site of a Bcl-2 mRNA.
18. The composition of claim 17, wherein the p-ethoxy oligonucleotide is an oligonucleotide comprising the sequence CAGCGTGCGCCATCCTTC (SEQ ID
NO:1).
19. The composition of claim 15, wherein the lipid is comprised in a liposome.
20. The composition of claim 19, wherein the p-ethoxy oligonucleotide is incorporated in the liposome.
21. The composition of claim 15, wherein the lipid is a phosphatidylcholine, a phosphatidylglycerol, or a phosphatidylethanolamine.
22. The composition of claim 21, wherein the lipid is dioleoylphosphatidylcholine.
23. The composition of claim 15, wherein the lipid is comprised in a lipid component that has a net neutral charge.
24. The composition of claim 15, wherein the lipid is comprised in a lipid component that has a net positive charge.
25. The composition of claim 15, wherein the lipid is comprised in a lipid component that has a net negative charge.
26. A composition comprising an expression construct that encodes a first polynucleotide that hybridizes to a second, Bcl-2-encoding polynucleotide under intracellular conditions, wherein the first polynucleotide comprises at least nucleotides and wherein the first polynucleotide is under the control of a promoter that is active in eukaryotic cells, and wherein said construct is associated with a lipid component, and further wherein the lipid component has a net neutral charge.
27. A use of a composition comprising a first polynucleotide that hybridizes to a second Bcl-2 encoding polynucleotide under intracellular conditions and a lipid component, wherein the first polynucleotide comprises at least 8 nucleotides and wherein the lipid component carries a net neutral charge, for inhibiting a Bcl-associated disease in a cell that expresses both Bcl-2 and Bax.
28. The use of claim 27, wherein the cell is a cancer cell.
29. The use of claim 28, wherein the cancer cell is a follicular lymphoma cell.
30. The use of claim 27, wherein the first polynucleotide is an oligonucleotide having a length of between about 8 and about 50 bases.
31. The use of claim 27, wherein the first polynucleotide is further defined as a p-ethoxy oligonucleotide.
32. The use of claim 27, wherein the first polynucleotide comprises a C-5 propyne pyrimidine.
33. The use of claim 27, wherein the C-5 propyne pyrimidine is a C-5 propyne analogue of uridine.
34. The use of claim 27, wherein the C-5 propyne pyrmidine is a C-5 propyne analogue of cytidine.
35. The use of claim 27, wherein the first polynucleotide is further defined as a methyl phosphonate oligonucleotide.
36. The of claim 27, wherein the lipid component is comprised in a liposome.
37. The use of claim 36, wherein the first polynucleotide is incorporated into the liposome.
38. The use of claim 27, wherein the composition further comprises a surfactant.
39. The use of claim 27, wherein the cell is in an animal.
40. The use of claim 39, wherein the animal is a human.
41. The use of claim 38, wherein the composition is to be used in a volume of 0.50-10.0 ml per dose.
42. The use of claim 40, wherein the composition is to be used in an amount of from about 5 to about 30 mg polynucleotide per m2.
43. The use of claim 27, wherein the lipid is a neutral lipid.
44. The use of claim 43, wherein the neutral lipid is a phosphatidylcholine, a phophatidylglycerol, or a phosphatidylethanolamine.
45. The use of claim 27, wherein the lipid is dioleoylphosphatidylcholine.
46. A use of a composition comprising a p-ethoxy oligonucleotide that hybridizes to a second Bcl-2 encoding polynucleotide under intracellular conditions and a lipid, wherein the p-ethoxy oligonucleotide comprises at least 8 nucleotides, for inhibiting a Bcl-2-associated disease in a cell that expresses both Bcl-2 and Bax.
47. The use of claim 46, wherein the cell is a cancer cell.
48. The use of claim 47, wherein the cancer cell is a follicular lymphoma cell.
49. The use of claim 46, wherein the p-ethoxy oligonucleotide is an oligonucleotide having a length of between about 8 and about 50 bases.
50. The use of claim 46, wherein the lipid component is comprised in a liposome.
51. The use of claim 50, wherein the p-ethoxy oligonucleotide is incorporated in the liposome.
52. The use of claim 46, wherein the cell is in an animal.
53. The use of claim 52, wherein the animal is a human.
54. The use of claim 53, wherein the composition is to be used in a volume of 0.50-10.0 ml per dose.
55. The use of claim 53, wherein the composition is to be used in an amount of from about 5 to about 30 mg polynucleotide per m2.
56. The use of claim 53, wherein the composition is to be used three times per week for eight weeks.
57. The use of claim 46, wherein the lipid is comprised in a lipid component that has a net neutral charge.
58. The use of claim 46, wherein the lipid is comprised in a lipid component that has a net positive charge.
59. The use of claim 46, wherein the lipid is comprised in a lipid component that has a net negative charge.
60. The use of claim 46, wherein the composition further comprises a surfactant.
CA2677176A 1996-10-04 1997-10-03 Inhibition of bcl-2 protein expression by liposomal antisense oligodeoxynucleotides Expired - Fee Related CA2677176C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/726,211 1996-10-04
US08/726,211 US6977244B2 (en) 1996-10-04 1996-10-04 Inhibition of Bcl-2 protein expression by liposomal antisense oligodeoxynucleotides
CA002266584A CA2266584C (en) 1996-10-04 1997-10-03 Inhibition of bcl-2 protein expression by liposomal antisense oligodeoxynucleotides

Related Parent Applications (1)

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CA002266584A Division CA2266584C (en) 1996-10-04 1997-10-03 Inhibition of bcl-2 protein expression by liposomal antisense oligodeoxynucleotides

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CA2677176A1 true CA2677176A1 (en) 1998-04-09
CA2677176C CA2677176C (en) 2013-01-08

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CA002266584A Expired - Fee Related CA2266584C (en) 1996-10-04 1997-10-03 Inhibition of bcl-2 protein expression by liposomal antisense oligodeoxynucleotides
CA2677176A Expired - Fee Related CA2677176C (en) 1996-10-04 1997-10-03 Inhibition of bcl-2 protein expression by liposomal antisense oligodeoxynucleotides

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US (2) US6977244B2 (en)
EP (1) EP0939621B1 (en)
JP (2) JP4402746B2 (en)
AT (1) ATE334657T1 (en)
CA (2) CA2266584C (en)
DE (1) DE69736432T2 (en)
ES (1) ES2270454T3 (en)
WO (1) WO1998014172A1 (en)

Families Citing this family (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5855911A (en) * 1995-08-29 1999-01-05 Board Of Regents, The University Of Texas System Liposomal phosphodiester, phosphorothioate, and P-ethoxy oligonucleotides
US6977244B2 (en) 1996-10-04 2005-12-20 Board Of Regents, The University Of Texas Systems Inhibition of Bcl-2 protein expression by liposomal antisense oligodeoxynucleotides
US7704962B1 (en) 1997-10-03 2010-04-27 Board Of Regents, The University Of Texas System Small oligonucleotides with anti-tumor activity
US7285288B1 (en) 1997-10-03 2007-10-23 Board Of Regents, The University Of Texas System Inhibition of Bcl-2 protein expression by liposomal antisense oligodeoxynucleotides
US20030171315A1 (en) * 2001-07-18 2003-09-11 Brown Bob D. Oligonucleotide probes and primers comprising universal bases for therapeutic purposes
US20040077082A1 (en) * 2002-10-18 2004-04-22 Koehn Richard K. RNA-based inhibitory oligonucleotides
JP4505749B2 (en) 2003-05-30 2010-07-21 日本新薬株式会社 Oligo double-stranded RNA that suppresses expression of Bcl-2 and pharmaceutical composition containing the same
US20060229267A1 (en) * 2004-06-01 2006-10-12 Reza Sheikhnejad Methods and compositions for the inhibition of gene expression
US8815599B2 (en) 2004-06-01 2014-08-26 Pronai Therapeutics, Inc. Methods and compositions for the inhibition of gene expression
EP1957045A2 (en) * 2005-03-14 2008-08-20 Board of Regents, The University of Texas System Bioactive fus1 peptides and nanoprticle-polypeptide complexes
CA2605068A1 (en) 2005-04-15 2006-10-26 The Board Of Regents Of The University Of Texas System Delivery of sirna by neutral lipid compositions
WO2007064945A2 (en) * 2005-12-01 2007-06-07 Pronai Therapeutics, Inc. Cancer therapies and pharmaceutical compositions used therein
WO2007065017A2 (en) * 2005-12-01 2007-06-07 Pronai Therapeutics, Inc. Oligonucleotide cationic liposomal delivery system
EP1957044B1 (en) * 2005-12-01 2013-03-13 Pronai Therapeutics, Inc. Amphoteric liposome formulation
US7850382B2 (en) 2007-01-18 2010-12-14 Sanford, L.P. Valve made from two materials and writing utensil with retractable tip incorporating same
US7488130B2 (en) 2007-02-01 2009-02-10 Sanford, L.P. Seal assembly for retractable instrument
WO2008103431A2 (en) * 2007-02-23 2008-08-28 Pronai Therapeutics, Inc. Dnai - liposomes
US8067390B2 (en) * 2007-03-02 2011-11-29 The Board Of Regents Of The University Of Texas System Therapeutic targeting of interleukins using siRNA in neutral liposomes
WO2009071681A2 (en) * 2007-12-07 2009-06-11 Santaris Pharma A/S Rna antagonist compounds for the modulation of bcl-2
US8226312B2 (en) 2008-03-28 2012-07-24 Sanford, L.P. Valve door having a force directing component and retractable instruments comprising same
WO2009149418A2 (en) * 2008-06-06 2009-12-10 Asuragen, Inc. Novel compositions for the in vivo delivery of rnai agents
US20100068235A1 (en) * 2008-09-16 2010-03-18 Searete LLC, a limited liability corporation of Deleware Individualizable dosage form
CN108165548B (en) * 2008-09-22 2022-10-14 菲奥医药公司 Reduced size self-delivering RNAi compounds
US8221012B2 (en) 2008-11-07 2012-07-17 Sanford, L.P. Retractable instruments comprising a one-piece valve door actuating assembly
US8393814B2 (en) 2009-01-30 2013-03-12 Sanford, L.P. Retractable instrument having a two stage protraction/retraction sequence
CN102686729B (en) 2009-12-18 2015-09-23 箭头研究公司 Be used for the treatment of the organic composite of HSF1 relative disease
MX2012009318A (en) 2010-02-10 2012-09-07 Novartis Ag Methods and compounds for muscle growth.
WO2011119852A1 (en) 2010-03-24 2011-09-29 Rxi Pharmaceuticals Corporation Reduced size self-delivering rnai compounds
EA034363B1 (en) 2010-04-23 2020-01-30 Эрроухед Фармасьютикалс, Инк. PHARMACEUTICAL COMPOSITION FOR INHIBITING BETA-ENaC GENE EXPRESSION AND USE THEREOF
EP3521432A1 (en) 2011-09-02 2019-08-07 Arrowhead Pharmaceuticals, Inc. Organic compositions to treat hsf1-related diseases
CA2860676A1 (en) 2012-01-09 2013-07-18 Novartis Ag Organic compositions to treat beta-catenin-related diseases
US9644205B2 (en) 2012-04-25 2017-05-09 The Regents Of The University Of California Synthetic promoter for modulating gene expression
EA201492004A1 (en) 2012-05-02 2015-08-31 Новартис Аг ORGANIC COMPOSITIONS FOR THE TREATMENT OF KRAS-ASSOCIATED DISEASES
WO2014071406A1 (en) * 2012-11-05 2014-05-08 Pronai Therapeutics, Inc. Methods of using biomarkers for the treatment of cancer by modulation of bcl2|expression
KR20150086294A (en) * 2012-11-05 2015-07-27 프로나이 테라퓨틱스, 인코포레이티드 Dosing and administration of oligonucleotide cancer therapies
US9868949B2 (en) 2013-02-28 2018-01-16 Arrowhead Pharmaceuticals, Inc. Organic compositions to treat EPAS1-related diseases
WO2015051135A2 (en) 2013-10-04 2015-04-09 Novartis Ag Organic compositions to treat hepcidin-related diseases
CN106061488B (en) 2013-12-02 2021-04-09 菲奥医药公司 Immunotherapy of cancer
EP3137119B1 (en) 2014-04-28 2020-07-01 Phio Pharmaceuticals Corp. Methods for treating cancer using a nucleic acid targeting mdm2
EP3169784B1 (en) 2014-07-16 2020-06-10 Arrowhead Pharmaceuticals, Inc. Rnai compositions to treat apoc3-related diseases
EP3191592A1 (en) 2014-09-11 2017-07-19 Novartis AG Inhibition of prmt5 to treat mtap-deficiency-related diseases
US10479997B2 (en) 2014-12-01 2019-11-19 Novartis Ag Compositions and methods for diagnosis and treatment of prostate cancer
WO2016193945A2 (en) 2015-06-05 2016-12-08 Novartis Ag Methods and compositions for diagnosing, treating, and monitoring treatment of shank3 deficiency associated disorders
KR20180091816A (en) 2015-10-14 2018-08-16 바이오-패쓰 홀딩스 인크. P-ethoxy nucleic acid for liposome preparation
WO2018047148A1 (en) 2016-09-12 2018-03-15 Novartis Ag Compounds for the inhibition of mirna
US10927379B2 (en) 2016-09-16 2021-02-23 Bio-Path Holdings, Inc. Combination therapy with liposomal antisense oligonucleotides
WO2018083606A1 (en) 2016-11-01 2018-05-11 Novartis Ag Methods and compositions for enhancing gene editing
US20210123058A1 (en) * 2017-04-19 2021-04-29 Bio-Path Holdings, Inc. P-ethoxy nucleic acids for bcl2 inhibition
CA3058018A1 (en) 2017-04-19 2018-10-25 Bio-Path Holdings, Inc. P-ethoxy nucleic acids for stat3 inhibition
WO2018195250A1 (en) * 2017-04-19 2018-10-25 Bio-Path Holdings, Inc. P-ethoxy nucleic acids for igf-1r inhibition
WO2019016772A2 (en) 2017-07-21 2019-01-24 Novartis Ag Compositions and methods to treat cancer
KR20200044013A (en) 2017-09-11 2020-04-28 애로우헤드 파마슈티컬스 인코포레이티드 RNAi agents and compositions for inhibiting expression of apolipoprotein C-III (APOC3)
WO2019150309A1 (en) 2018-02-02 2019-08-08 Hammack Scott Modulators of gpr68 and uses thereof for treating and preventing diseases
US20210123016A1 (en) 2018-05-02 2021-04-29 Novartis Ag Regulators of human pluripotent stem cells and uses thereof

Family Cites Families (90)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US598635A (en) * 1898-02-08 Water-purifier
CH621479A5 (en) 1977-08-05 1981-02-13 Battelle Memorial Institute
US4394448A (en) 1978-02-24 1983-07-19 Szoka Jr Francis C Method of inserting DNA into living cells
US4469863A (en) 1980-11-12 1984-09-04 Ts O Paul O P Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof
US4480041A (en) 1982-07-09 1984-10-30 Collaborative Research, Inc. Use of phosphotriester intermediates for preparation of functionalized liposomes
FR2540122B1 (en) 1983-01-27 1985-11-29 Centre Nat Rech Scient NOVEL COMPOUNDS COMPRISING A SEQUENCE OF OLIGONUCLEOTIDE LINKED TO AN INTERCALATION AGENT, THEIR SYNTHESIS PROCESS AND THEIR APPLICATION
US4721612A (en) 1984-04-12 1988-01-26 The Liposome Company, Inc. Steroidal liposomes
US5015568A (en) 1986-07-09 1991-05-14 The Wistar Institute Diagnostic methods for detecting lymphomas in humans
US5202429A (en) 1986-07-09 1993-04-13 The Wistar Institute DNA molecules having human BCL-2 gene sequences
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US5094785A (en) 1986-12-10 1992-03-10 Ciba Corning Diagnostics Corp. Process for stabilizing liposomes
US4920016A (en) 1986-12-24 1990-04-24 Linear Technology, Inc. Liposomes with enhanced circulation time
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5030442A (en) 1987-03-30 1991-07-09 Liposome Technology, Inc. Non-crystalline minoxidil composition
US4904582A (en) 1987-06-11 1990-02-27 Synthetic Genetics Novel amphiphilic nucleic acid conjugates
US4950432A (en) 1987-10-16 1990-08-21 Board Of Regents, The University Of Texas System Polyene microlide pre-liposomal powders
US5178875A (en) 1991-01-14 1993-01-12 The Board Of Regents, The University Of Texas System Liposomal-polyene preliposomal powder and method for its preparation
US5188897A (en) 1987-10-22 1993-02-23 Temple University Of The Commonwealth System Of Higher Education Encapsulated 2',5'-phosphorothioate oligoadenylates
US4924624A (en) 1987-10-22 1990-05-15 Temple University-Of The Commonwealth System Of Higher Education 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof
EP0397774A1 (en) 1988-02-04 1990-11-22 Board Of Regents, The University Of Texas System Formulation and use of retinoids in treatment of cancer and other diseases
US5098890A (en) 1988-11-07 1992-03-24 Temple University-Of The Commonwealth System Of Higher Education Antisence oligonucleotides to c-myb proto-oncogene and uses thereof
US5831066A (en) 1988-12-22 1998-11-03 The Trustees Of The University Of Pennsylvania Regulation of bcl-2 gene expression
US5734033A (en) 1988-12-22 1998-03-31 The Trustees Of The University Of Pennsylvania Antisense oligonucleotides inhibiting human bcl-2 gene expression
US5248671A (en) 1989-02-15 1993-09-28 Board Of Regents, The University Of Texas System Methods and compositions for treatment of cancer using oligonucleotides
US5087617A (en) 1989-02-15 1992-02-11 Board Of Regents, The University Of Texas System Methods and compositions for treatment of cancer using oligonucleotides
FR2644080A1 (en) 1989-03-13 1990-09-14 Trizac Jacques DEVICE FOR FILTRATION AND EVACUATION OF SMALL PARTICLES, WASTES AND TRENDS OF VARIOUS NATURE
WO1990012595A1 (en) 1989-04-18 1990-11-01 Vestar, Inc. Liposomal targeting of ischemic tissue
US5112962A (en) 1989-04-19 1992-05-12 Northwestern University Labile anchors for solid phase polynucleotide synthesis
US5227170A (en) 1989-06-22 1993-07-13 Vestar, Inc. Encapsulation process
US5100662A (en) 1989-08-23 1992-03-31 The Liposome Company, Inc. Steroidal liposomes exhibiting enhanced stability
WO1993007883A1 (en) 1991-10-24 1993-04-29 Isis Pharmaceuticals, Inc. Derivatized oligonucleotides having improved uptake and other properties
CA2033725C (en) 1990-01-24 2001-05-29 Folker Pittrof Pharmaceutical and cosmetic compositions containing a salt of cholanic acid
US5279833A (en) 1990-04-04 1994-01-18 Yale University Liposomal transfection of nucleic acids into animal cells
US5264618A (en) 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
US5665710A (en) 1990-04-30 1997-09-09 Georgetown University Method of making liposomal oligodeoxynucleotide compositions
EP0527818A4 (en) 1990-04-30 1993-09-15 Isis Pharmaceuticals, Inc. Oligonucleotide modulation of arachidonic acid metabolism
ATE151076T1 (en) 1990-07-02 1997-04-15 Hoechst Ag OLIGONUCLEOTIDE ANALOGUES WITH TERMINALS 3'-3' OR 5'-5' INTERNUCLEOTIDE LINKAGES
US5135917A (en) 1990-07-12 1992-08-04 Nova Pharmaceutical Corporation Interleukin receptor expression inhibiting antisense oligonucleotides
US5378825A (en) 1990-07-27 1995-01-03 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogs
EP0556231A4 (en) 1990-09-17 1994-08-17 Univ California Method and composition for controlling proliferation of cells
US5271941A (en) 1990-11-02 1993-12-21 Cho Chung Yoon S Antisense oligonucleotides of human regulatory subunit RI.sub.α of cAMP-dependent protein kinases
FR2677272B1 (en) 1991-06-05 1995-03-03 Biovecteurs As PARTICULATE VECTOR WITH SELECTIVE TROPISM, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITION.
US5525719A (en) * 1991-08-30 1996-06-11 Chemgenes Corporation N-protected-2'-O-methyl-and N-protected-3'-O-methyl-ribonucleosides and their phosphoramidite derivatives
US6030954A (en) 1991-09-05 2000-02-29 University Of Connecticut Targeted delivery of poly- or oligonucleotides to cells
DE69233118T2 (en) 1991-12-04 2004-04-15 E.I. Du Pont De Nemours And Co., Wilmington FATTY ACID DESATURASE GENES FROM PLANTS
US5858784A (en) 1991-12-17 1999-01-12 The Regents Of The University Of California Expression of cloned genes in the lung by aerosol- and liposome-based delivery
WO1993020200A1 (en) * 1992-04-02 1993-10-14 Imperial Cancer Research Technology Limited Modified cells and method of treatment
US5279957A (en) 1992-04-30 1994-01-18 Washington University cDNA encoding human phospholipase A2 polypeptide
IT1255770B (en) 1992-05-22 1995-11-15 Consiglio Nazionale Ricerche ANTISENSE OLIGONUCLEOTIDES FOR ANTI-CANCER ACTIVITIES, PHARMACEUTICAL COMPOSITIONS THAT INCLUDE THEM, AND THEIR USE
US5320962A (en) 1992-07-22 1994-06-14 Duke University DNA encoding the human A1 adenosine receptor
NL9201440A (en) 1992-08-11 1994-03-01 Univ Leiden Triantennary cluster glycosides, their preparation and application.
AU5092893A (en) 1992-09-02 1994-03-29 Georgetown University Method of encapsulating anthracycline glycosides in liposomes
US6001992A (en) 1999-01-07 1999-12-14 Isis Pharmaceuticals Inc. Antisense modulation of novel anti-apoptotic bcl-2-related proteins
US6015886A (en) 1993-05-24 2000-01-18 Chemgenes Corporation Oligonucleotide phosphate esters
US5417978A (en) 1993-07-29 1995-05-23 Board Of Regents, The University Of Texas System Liposomal antisense methyl phosphonate oligonucleotides and methods for their preparation and use
US5539085A (en) 1993-08-20 1996-07-23 Onyx Pharmaceuticals, Inc. Bcl-2 and R-ras complex
US5622852A (en) 1994-10-31 1997-04-22 Washington University Bcl-x/Bcl-2 associated cell death regulator
FR2710074B1 (en) 1993-09-15 1995-12-08 Rhone Poulenc Rorer Sa GRB3-3 gene, its variants and their uses.
EP1584682B1 (en) * 1993-09-20 2009-07-15 The Trustees Of The University Of Pennsylvania Regulation of bcl-2 gene expression
US5539094A (en) 1993-11-12 1996-07-23 La Jolla Cancer Research Foundation DNA encoding Bcl-2-associated proteins
US5583034A (en) * 1994-02-22 1996-12-10 La Jolla Institute For Allergy And Immunology Enhancement of adoptosis using antisense oligonucleotides
US5651981A (en) 1994-03-29 1997-07-29 Northwestern University Cationic phospholipids for transfection
WO1995028497A1 (en) 1994-04-13 1995-10-26 La Jolla Cancer Research Foundation Interaction of proteins involved in a cell death pathway
US5696248A (en) 1994-06-15 1997-12-09 Hoechst Aktiengesellschaft 3'-modified oligonucleotide derivatives
US5908635A (en) 1994-08-05 1999-06-01 The United States Of America As Represented By The Department Of Health And Human Services Method for the liposomal delivery of nucleic acids
US5565337A (en) 1994-08-23 1996-10-15 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Hybridoma-producing NSO myeloma cell line
IT1275862B1 (en) 1995-03-03 1997-10-24 Consiglio Nazionale Ricerche ANTI-SENSE TRANSCRIPT ASSOCIATED WITH SOME TYPES OF TUMOR CELLS AND SYNTHETIC OLIGODEOXYNUCLEOTIDES USEFUL IN DIAGNOSIS AND TREATMENT
PT739898E (en) 1995-03-13 2002-03-28 Aventis Pharma Gmbh PHOSPHONUCLETIC ACID MONO-ESTERS PROCESS FOR PREPARING AND USING
ATE332710T1 (en) 1995-06-01 2006-08-15 Kishimoto Tadamitsu GROWTH INHIBITOR AGAINST LEUKEMIC CELLS CONTAINING ANTISENSE OLIGONUCLEOTIDE DERIVATIVES AGAINST WILMS TUMOR
US6326487B1 (en) 1995-06-05 2001-12-04 Aventis Pharma Deutschland Gmbh 3 modified oligonucleotide derivatives
US5981501A (en) 1995-06-07 1999-11-09 Inex Pharmaceuticals Corp. Methods for encapsulating plasmids in lipid bilayers
AU723163B2 (en) 1995-06-07 2000-08-17 Tekmira Pharmaceuticals Corporation Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer
US5756122A (en) 1995-06-07 1998-05-26 Georgetown University Liposomally encapsulated nucleic acids having high entrapment efficiencies, method of manufacturer and use thereof for transfection of targeted cells
US5705385A (en) 1995-06-07 1998-01-06 Inex Pharmaceuticals Corporation Lipid-nucleic acid particles prepared via a hydrophobic lipid-nucleic acid complex intermediate and use for gene transfer
AU705644B2 (en) 1995-08-01 1999-05-27 Novartis Ag Liposomal oligonucleotide compositions
US5855911A (en) 1995-08-29 1999-01-05 Board Of Regents, The University Of Texas System Liposomal phosphodiester, phosphorothioate, and P-ethoxy oligonucleotides
DE19532553A1 (en) 1995-09-04 1997-03-06 Hoechst Ag Process for the preparation of substituted N-ethyl-glycine derivatives
US6120794A (en) 1995-09-26 2000-09-19 University Of Pittsburgh Emulsion and micellar formulations for the delivery of biologically active substances to cells
US6958239B2 (en) 1996-11-21 2005-10-25 Oligos Etc Inc. Three component chimeric antisense oligonucleotides
US6977244B2 (en) 1996-10-04 2005-12-20 Board Of Regents, The University Of Texas Systems Inhibition of Bcl-2 protein expression by liposomal antisense oligodeoxynucleotides
US5874224A (en) 1997-03-11 1999-02-23 Incyte Pharmaceuticals, Inc. Growth factor receptor binding protein
US5837838A (en) 1997-03-14 1998-11-17 The Burnham Institute Bax inhibitor proteins
US6126965A (en) 1997-03-21 2000-10-03 Georgetown University School Of Medicine Liposomes containing oligonucleotides
GB9711919D0 (en) 1997-06-09 1997-08-06 Ciba Geigy Ag Oligonucleotide derivatives
JP2002508765A (en) 1997-06-23 2002-03-19 アルザ コーポレイション Liposome-encapsulated polynucleotide compositions and methods
AU8280798A (en) 1997-07-03 1999-01-25 Thomas Jefferson University An improved method for design and selection of efficacious antisense oligonucleotides
US6136965A (en) 1998-07-02 2000-10-24 The Regents Of The University Of California Deoxynucleic alkyl and alkoxy thiourea compounds
US6211162B1 (en) 1998-12-30 2001-04-03 Oligos Etc. Inc. Pulmonary delivery of protonated/acidified nucleic acids
US6211349B1 (en) 1998-12-30 2001-04-03 Oligos Etc., Inc. Protonated/acidified nucleic acids and methods of use
US7795232B1 (en) 2000-08-25 2010-09-14 Genta Incorporated Methods of treatment of a bcl-2 disorder using bcl-2 antisense oligomers

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