RU2018136611A - Генная терапия для лечения гемофилии a - Google Patents
Генная терапия для лечения гемофилии a Download PDFInfo
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- RU2018136611A RU2018136611A RU2018136611A RU2018136611A RU2018136611A RU 2018136611 A RU2018136611 A RU 2018136611A RU 2018136611 A RU2018136611 A RU 2018136611A RU 2018136611 A RU2018136611 A RU 2018136611A RU 2018136611 A RU2018136611 A RU 2018136611A
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- Prior art keywords
- raav
- virus according
- aav
- seq
- capsid
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- 208000009292 Hemophilia A Diseases 0.000 title claims 5
- 208000031220 Hemophilia Diseases 0.000 title 1
- 238000001415 gene therapy Methods 0.000 title 1
- 241000700605 Viruses Species 0.000 claims 12
- 241000702421 Dependoparvovirus Species 0.000 claims 10
- 210000000234 capsid Anatomy 0.000 claims 8
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims 7
- 239000000725 suspension Substances 0.000 claims 5
- 102100026735 Coagulation factor VIII Human genes 0.000 claims 4
- 108091026890 Coding region Proteins 0.000 claims 4
- 201000003542 Factor VIII deficiency Diseases 0.000 claims 4
- 108010071690 Prealbumin Proteins 0.000 claims 4
- 102000009190 Transthyretin Human genes 0.000 claims 4
- 102000057593 human F8 Human genes 0.000 claims 3
- 229960000900 human factor viii Drugs 0.000 claims 3
- 239000007900 aqueous suspension Substances 0.000 claims 2
- 230000015271 coagulation Effects 0.000 claims 2
- 238000005345 coagulation Methods 0.000 claims 2
- 239000003623 enhancer Substances 0.000 claims 2
- 239000007788 liquid Substances 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- 230000001225 therapeutic effect Effects 0.000 claims 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 1
- 241000702423 Adeno-associated virus - 2 Species 0.000 claims 1
- 108010054218 Factor VIII Proteins 0.000 claims 1
- 102000001690 Factor VIII Human genes 0.000 claims 1
- 238000011529 RT qPCR Methods 0.000 claims 1
- 150000001413 amino acids Chemical class 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229960000301 factor viii Drugs 0.000 claims 1
- 238000010253 intravenous injection Methods 0.000 claims 1
- 239000002773 nucleotide Substances 0.000 claims 1
- 125000003729 nucleotide group Chemical group 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 239000004094 surface-active agent Substances 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
- A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
-
- 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
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
-
- 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
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- 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
- C12N7/00—Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof
-
- 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
- C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14132—Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Wood Science & Technology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Hematology (AREA)
- Virology (AREA)
- Microbiology (AREA)
- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Plant Pathology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (31)
1. Рекомбинатный аденоассоциированный вирус (rAAV), используемый как направленное на печень терапевтическое средство для лечения гемофилии A, причем указанный rAAV содержит капсид AAV и упакованный в него векторный геном, при этом указанный векторный геном содержит
(a) последовательность AAV с 5' инвертированным концевым повтором (ITR);
(b) энхансер транстиретина (enTTR);
(c) промотор транстиретина (TTR);
(d) кодирующую последовательность, кодирующую человеческий фактор VIII, обеспечивающий функцию обеспечения коагуляции;
(e) 3' ITR AAV.
2. Вирус rAAV по п. 1, отличающийся тем, что человеческий фактор VIII представляет собой фактор VIII SQ с удаленным B-доменом, содержащий в длину около 1457 аминокислот.
3. Вирус rAAV по п. 1 или п. 2, отличающийся тем, что кодирующая последовательность из (d) выбрана из SEQ ID NO: 1 и SEQ ID NO: 2.
4. Вирус rAAV по любому из пп. 1–3, отличающийся тем, что капсид rAAV представляет собой капсид hu37.
5. Вирус rAAV по любому из пп. 1–4, отличающийся тем, что 5' ITR AAV и/или 3' ITR AAV взяты из AAV2.
6. Вирус rAAV по любому из пп. 1–5, отличающийся тем, что векторный геном дополнительно содержит полиA, которая имеет размер около 75 п. н.
7. Вирус rAAV по любому из пп. 1–6, отличающийся тем, что векторный геном имеет размер от около 5 т. п. н. до около 5,5 т. п. н.
8. Водная суспензия, пригодная для введения пациенту с гемофилией A, причем указанная суспензия содержит водную суспендирующую жидкость и от около 1 x1012 ГК/мл до около 1 x1014 ГК/мл рекомбинатного аденоассоциированного вируса (rAAV), используемого как направленное на печень терапевтическое средство для лечения гемофилии A, при этом указанный rAAV содержит капсид AAV и упакованный в него векторный геном, содержащий
(a) последовательность AAV с 5' инвертированным концевым повтором (ITR);
(b) энхансер транстиретина (enTTR);
(c) промотор транстиретина (TTR);
(d) кодирующую последовательность, кодирующую человеческий фактор VIII, обеспечивающий функцию обеспечения коагуляции;
(e) 3' ITR AAV.
9. Суспензия по п. 8, отличающаяся тем, что суспензия пригодна для внутривенной инъекции.
10. Суспензия по п. 8 или п. 9, отличающаяся тем, что суспензия дополнительно содержит поверхностно-активное вещество, консервант и/или буфер, растворенные в водной суспендирующей жидкости.
11. Способ лечения пациента с гемофилией A с использованием rAAV по п. 1, в котором rAAV доставляют в водной суспензии в дозе от около 1 x 1012 до около 1 x 1014 геномных копий (ГК)/кг, причем ГК рассчитывают при определении на основе окПЦР (оптимизированная кПЦР).
12. Способ по п. 11, отличающийся тем, что rAAV вводят повторно в более поздний момент времени.
13. Вирус rAAV по п. 1, отличающийся тем, что векторный геном содержит нуклеотиды 1–5110 из SEQ ID NO: 13.
14. Вирус rAAV по п. 13, отличающийся тем, что капсид rAAV представляет собой капсид hu37.
15. Вирус rAAV по п. 1, отличающийся тем, что
enTTR представляет собой SEQ ID NO:5;
промотор TTR представляет собой SEQ ID NO:7;
кодирующая последовательность представляет собой SED ID NO:2.
16. Вирус rAAV по п. 15, отличающийся тем, что 5' ITR AAV представляет собой SEQ ID NO:11, а 3' ITR AAV представляет собой SEQ ID NO:12.
17. Вирус rAAV по любому из пп. 15 или 16, дополнительно содержащий последовательность полиA SEQ ID NO:10.
18. Вирус rAAV по любому из пп. 15–17, отличающийся тем, что капсид rAAV представляет собой капсид hu37.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662323336P | 2016-04-15 | 2016-04-15 | |
| US62/323,336 | 2016-04-15 | ||
| US201662331807P | 2016-05-04 | 2016-05-04 | |
| US62/331,807 | 2016-05-04 | ||
| US201662428866P | 2016-12-01 | 2016-12-01 | |
| US62/428,866 | 2016-12-01 | ||
| PCT/US2017/027396 WO2017180857A1 (en) | 2016-04-15 | 2017-04-13 | Gene therapy for treating hemophilia a |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| RU2018136611A true RU2018136611A (ru) | 2020-05-15 |
| RU2018136611A3 RU2018136611A3 (ru) | 2020-08-11 |
| RU2762257C2 RU2762257C2 (ru) | 2021-12-17 |
Family
ID=59253992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2018136611A RU2762257C2 (ru) | 2016-04-15 | 2017-04-13 | Генная терапия для лечения гемофилии a |
Country Status (17)
| Country | Link |
|---|---|
| US (3) | US11779656B2 (ru) |
| EP (1) | EP3452102B9 (ru) |
| JP (2) | JP7347933B2 (ru) |
| KR (1) | KR102450833B1 (ru) |
| CN (1) | CN109562191A (ru) |
| AU (1) | AU2017248659B2 (ru) |
| BR (1) | BR112018071200A2 (ru) |
| CA (1) | CA3019425A1 (ru) |
| IL (1) | IL262215B2 (ru) |
| MX (1) | MX2018012537A (ru) |
| PE (2) | PE20250736A1 (ru) |
| RU (1) | RU2762257C2 (ru) |
| SA (1) | SA518400233B1 (ru) |
| SG (2) | SG11201808422QA (ru) |
| TW (1) | TWI791433B (ru) |
| WO (1) | WO2017180857A1 (ru) |
| ZA (1) | ZA201806477B (ru) |
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| JP7418957B2 (ja) | 2015-11-16 | 2024-01-22 | リサーチ インスティチュート アット ネイションワイド チルドレンズ ホスピタル | タイチン系ミオパチー及び他のタイチノパチーの治療のための材料及び方法 |
| EP3442597A1 (en) | 2016-04-15 | 2019-02-20 | The Trustees Of The University Of Pennsylvania | Gene therapy for treating hemophilia b |
| KR102450833B1 (ko) * | 2016-04-15 | 2022-10-05 | 더 트러스티스 오브 더 유니버시티 오브 펜실베니아 | 혈우병 a 치료용 유전자 요법 |
| BR112020015173A2 (pt) | 2018-01-31 | 2020-12-29 | Research Institute At Nationwide Children's Hospital | Terapia gênica para distrofia muscular da cintura e membros do tipo 2c |
| KR20210028162A (ko) | 2018-06-29 | 2021-03-11 | 더 리서치 인스티튜트 앳 네이션와이드 칠드런스 하스피탈 | 지대근 이영양증 2a형을 치료하기 위한 재조합 아데노 연관 바이러스 생성물 및 방법 |
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| KR20210076051A (ko) * | 2018-10-12 | 2021-06-23 | 젠자임 코포레이션 | 간-특이적 유전자 대체 요법에 의한 중증 pku 치료를 위한 개선된 인간 pah의 생성 |
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| AU2019360182B2 (en) | 2018-10-16 | 2023-02-16 | Blueallele Corporation | Methods for targeted insertion of DNA in genes |
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| TWI851647B (zh) * | 2019-01-16 | 2024-08-11 | 日商武田藥品工業股份有限公司 | 用於a型血友病基因治療之編碼表現增加之重組fviii變異體的病毒載體 |
| SG11202109113TA (en) * | 2019-02-26 | 2021-09-29 | Res Inst Nationwide Childrens Hospital | Adeno-associated virus vector delivery of b-sarcoglycan and the treatment of muscular dystrophy |
| BR112021017853A2 (pt) | 2019-03-13 | 2021-11-30 | Generation Bio Co | Vetores de dna não virais e usos dos mesmos para expressar terapêuticas de fviii |
| PL4017871T3 (pl) | 2019-08-21 | 2024-07-08 | Research Institute At Nationwide Children's Hospital | Dostarczanie alfa-sarkoglikanu za pomocą wektora wirusa związanego z adenowirusami i leczenie dystrofii mięśniowej |
| EP4051703A1 (en) * | 2019-11-01 | 2022-09-07 | Freeline Therapeutics Limited | Factor viii polypeptide |
| CN111218446B (zh) * | 2019-12-25 | 2023-03-28 | 劲帆生物医药科技（武汉）有限公司 | 一种肝脏特异性启动子及其应用 |
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