JP5174039B2 - C型肝炎ウイルス感染の治療 - Google Patents
C型肝炎ウイルス感染の治療 Download PDFInfo
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- JP5174039B2 JP5174039B2 JP2009547354A JP2009547354A JP5174039B2 JP 5174039 B2 JP5174039 B2 JP 5174039B2 JP 2009547354 A JP2009547354 A JP 2009547354A JP 2009547354 A JP2009547354 A JP 2009547354A JP 5174039 B2 JP5174039 B2 JP 5174039B2
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- C—CHEMISTRY; METALLURGY
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- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
- C12Q1/025—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
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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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- 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
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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
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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
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- 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
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/24011—Flaviviridae
- C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
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- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Wood Science & Technology (AREA)
- Biomedical Technology (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Plant Pathology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Toxicology (AREA)
- Analytical Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
この研究は、National Institute of Health交付番号5 P01 HL20948−30(題名、Molecular Basis of Cholesterol Metabolism)により支援されている。米国政府はこの出願において生ずるあらゆる特許において権利を有し得る。
発明者らは、a)VLDLアセンブリ阻害剤と細胞を接触させることと;b)細胞からのHCV放出の生じた阻害を検出することと、を含む、HCV感染細胞からのC型肝炎ウイルス(HCV)の放出を阻害する方法を記載する。
発明者らは、Huh7−GL細胞、染色体に組み込まれた遺伝子型2aHCV cDNAを含有し、感染性ウイルスを構成的に産生するHuh7細胞の株(Caiら、2005)に、apoB又は対照としてGFPを標的とする二重siRNAを遺伝子移入した。血清不含培地中での温置後、培養液を回収し、培地中のapoB及びHCVの量を分析した。apoB siRNAでの細胞の遺伝子移入により、細胞内HCV RNAに影響を与えずに、apoB mRNAの量を約80%減少させた。apoB siRNAにより、培地中に分泌されるapoBの量が顕著に減少したが、α1−アンチトリプシンの分泌には影響がなかった。GFP siRNAで遺伝子移入した対照細胞において、HCVコピー数及び力価は、4時間の温置時間の間、10倍を超えて上昇した。apoB siRNAを受容した細胞において、ウイルスコピー数によりアッセイした場合、この上昇は約50%低下し、ウイルス力価によりアッセイした場合、70%低下した。
MTP阻害剤BMS−201038の存在下又は非存在下でHuh7−GL細胞を温置した。血清不含培地中での温置後、培養液を回収し、培地中のHCV RNA、HCV力価及びapoBの量を測定した。MTP阻害剤との細胞の温置により、apoBの分泌は阻止されたが、α1−アンチトリプシンは阻止されなかった。MTP阻害剤での細胞の処理により、培地中のHCV RNAの量及びウイルス力価が約80%減少した。細胞内HCV RNAはMTP阻害剤の非存在下又は存在下で同じままであるので、培地中のHCV量の減少はHCV RNA合成の阻害によるものではない。阻害剤とともに温置しなかった細胞においてでさえも培地中で検出されるHCV RNAの量は細胞において見られる量の1%未満であったので、発明者らは、MTP阻害剤で処理した細胞において細胞内HCV RNAの蓄積を観察しなかった。
実施例2に記載のようにHuh7−GL細胞を培養する。第1日に、次のMTP阻害剤:BMS−201038(陽性対照)、BMS−200150、BMS−212122、BMS−197636、JTT−130、インプリタピド、ミトラタピド及びCP−346086の、1nM、10nM、100nM及び500nMで細胞を処理する。16時間後、第2日に、同量のMTP阻害剤の非存在下又は存在下で細胞の培地を血清不含培地に交換する。4時間温置した後、上記で調べたような培地中でのHCV RNAコピー数及び力価の低下により、試験した各阻害剤に対するウイルスの細胞放出の減少が明らかになる。
インターフェロン単剤療法に無反応であったか不耐であった慢性HCV感染患者でのBMS201038の効能及び安全性を評価するために、無作為二重盲検プラセボ対照試験(Raymondら、Ann Intern Med.(1998)11月15日;129(10):797−800)を使用する。
Claims (6)
- HCV感染細胞からのHCVの放出を阻害する方法に使用するための、VLDLアセンブリ阻害剤を含む剤形であって、前記方法が、
a)VLDLアセンブリ阻害剤と細胞を接触させることと;及び
b)細胞からのHCV放出の生じた阻害を検出することと、
を含み、
前記VLDLアセンブリ阻害剤が、BMS−201038(AERG−733)、及びアポリポタンパク質Bに対する低分子干渉RNA(siRNA)からなる群より選択される、剤形。 - HCV感染細胞からのHCVの放出を阻害する前記方法の接触段階が、インターフェロン及びリバビリンから選択される抗ウイルス剤に細胞を接触させることをさらに含む、請求項1に記載の剤形。
- HCV感染者の血清ウイルス血症を低下させる方法に使用するための、VLDLアセンブリ阻害剤を含む剤形であって、前記方法が、
a)VLDLアセンブリ阻害剤をHCV感染者に投与することと;及び
b)HCV感染者における血清ウイルス血症の生じた低下を検出することとを含み、
前記VLDLアセンブリ阻害剤が、BMS−201038(AERG−733)、及びアポリポタンパク質Bに対する低分子干渉RNA(siRNA)からなる群より選択される、剤形。 - HCV感染者の血清ウイルス血症を低下させる前記方法の投与段階が、インターフェロン及びリバビリンから選択される抗ウイルス剤を感染者に投与することをさらに含む、請求項3に記載の剤形。
- マイクロモル以下の濃度のVLDLアセンブリ阻害剤によって血清ウイルス血症を低下させ、該濃度が、血清ウイルス血症を低下させるのに十分な時間、該阻害剤の1日あたり1mg/kg体重以下をヒトに投与することによって達成される、請求項3に記載の剤形。
- マイクロモル以下の濃度のVLDLアセンブリ阻害剤によって血清ウイルス血症を低下させ、該濃度が、血清ウイルス血症を低下させるのに十分な時間、該阻害剤の1日あたり0.1mg/kg体重以下をヒトに投与することによって達成される、請求項3に記載の剤形。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/657,856 US7645732B2 (en) | 2007-01-24 | 2007-01-24 | Treating hepatitis C virus infection |
US11/657,856 | 2007-01-24 | ||
PCT/US2008/051097 WO2008091763A1 (en) | 2007-01-24 | 2008-01-15 | Treating hepatitis c virus infection |
Related Child Applications (1)
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JP2012220962A Division JP5745488B2 (ja) | 2007-01-24 | 2012-10-03 | C型肝炎ウイルス感染の治療 |
Publications (2)
Publication Number | Publication Date |
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JP2010516776A JP2010516776A (ja) | 2010-05-20 |
JP5174039B2 true JP5174039B2 (ja) | 2013-04-03 |
Family
ID=39641451
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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JP2009547354A Expired - Fee Related JP5174039B2 (ja) | 2007-01-24 | 2008-01-15 | C型肝炎ウイルス感染の治療 |
JP2012220962A Expired - Fee Related JP5745488B2 (ja) | 2007-01-24 | 2012-10-03 | C型肝炎ウイルス感染の治療 |
Family Applications After (1)
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JP2012220962A Expired - Fee Related JP5745488B2 (ja) | 2007-01-24 | 2012-10-03 | C型肝炎ウイルス感染の治療 |
Country Status (6)
Country | Link |
---|---|
US (3) | US7645732B2 (ja) |
EP (1) | EP2120988A4 (ja) |
JP (2) | JP5174039B2 (ja) |
AU (1) | AU2008209338B2 (ja) |
CA (1) | CA2675764C (ja) |
WO (1) | WO2008091763A1 (ja) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL1725234T5 (pl) | 2004-03-05 | 2016-06-30 | Univ Pennsylvania | Sposoby leczenia zaburzeń lub chorób związanych z hiperlipidemią i hipercholesterolemią ze zminimalizowaniem efektów ubocznych |
WO2008079398A1 (en) * | 2006-12-21 | 2008-07-03 | Aegerion Pharmaceuticals, Inc. | Methods for treating obesity with a combination comprising a mtp inhibitor and a cholesterol absorption inhibitor |
WO2008124384A2 (en) * | 2007-04-03 | 2008-10-16 | Aegerion Pharmaceuticals, Inc. | Combinations of mtp inhibitors with cholesterol absorption inhibitors or interferon for treating hepatitis c |
US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
UY34402A (es) | 2011-10-21 | 2013-05-31 | Abbvie Inc | Métodos para el tratamiento de hcv |
US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
CH707030B1 (de) | 2011-10-21 | 2015-03-13 | Abbvie Inc | Kombinationsbehandlung von DAAs zur Verwendung in der Behandlung von HCV |
EP3448392A4 (en) | 2016-04-28 | 2020-01-15 | Emory University | ALCYNE-CONTAINING NUCLEOTIDES AND NUCLEOSIDES THERAPEUTIC COMPOSITIONS AND USES THEREOF |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2840921B1 (fr) * | 2002-06-18 | 2008-07-18 | Bio Merieux | Procede de culture in vitro du virus vhc |
US20090042835A1 (en) * | 2006-06-02 | 2009-02-12 | Davis Roger A | Compositions and methods for ameliorating hyperlipidemia |
US20080241869A1 (en) * | 2006-06-02 | 2008-10-02 | San Diego State University Research Foundation | Compositions and methods for ameliorating hyperlipidemia |
US20100310553A1 (en) * | 2006-08-14 | 2010-12-09 | Guangxiang Luo | Compositions and Methods for Controlling Hepatitis C Virus Infection |
-
2007
- 2007-01-24 US US11/657,856 patent/US7645732B2/en not_active Expired - Fee Related
-
2008
- 2008-01-15 CA CA2675764A patent/CA2675764C/en not_active Expired - Fee Related
- 2008-01-15 AU AU2008209338A patent/AU2008209338B2/en not_active Ceased
- 2008-01-15 EP EP08727697A patent/EP2120988A4/en not_active Withdrawn
- 2008-01-15 JP JP2009547354A patent/JP5174039B2/ja not_active Expired - Fee Related
- 2008-01-15 WO PCT/US2008/051097 patent/WO2008091763A1/en active Application Filing
-
2009
- 2009-12-07 US US12/631,917 patent/US20100203013A1/en not_active Abandoned
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2012
- 2012-10-03 JP JP2012220962A patent/JP5745488B2/ja not_active Expired - Fee Related
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2013
- 2013-02-12 US US13/765,506 patent/US8987189B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
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US20080175864A1 (en) | 2008-07-24 |
AU2008209338A1 (en) | 2008-07-31 |
EP2120988A4 (en) | 2011-02-23 |
US20140056846A1 (en) | 2014-02-27 |
US7645732B2 (en) | 2010-01-12 |
CA2675764A1 (en) | 2008-07-31 |
EP2120988A1 (en) | 2009-11-25 |
WO2008091763A1 (en) | 2008-07-31 |
JP5745488B2 (ja) | 2015-07-08 |
AU2008209338B2 (en) | 2010-05-13 |
US20100203013A1 (en) | 2010-08-12 |
JP2010516776A (ja) | 2010-05-20 |
US8987189B2 (en) | 2015-03-24 |
JP2013047237A (ja) | 2013-03-07 |
CA2675764C (en) | 2015-06-16 |
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