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1. (WO2019066518) COMPOSITION FOR TREATMENT OF HEMOPHILIA, COMPRISING CRISPR/CAS SYSTEM HAVING COAGULATION FACTOR VIII GENE INVERSION CORRECTION POTENTIAL
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Pub. No.: WO/2019/066518 International Application No.: PCT/KR2018/011480
Publication Date: 04.04.2019 International Filing Date: 28.09.2018
IPC:
C12N 15/113 (2010.01) ,C12N 9/22 (2006.01) ,C12N 15/10 (2006.01) ,C12N 15/86 (2006.01) ,C12N 15/90 (2006.01) ,A61K 48/00 (2006.01) ,A61P 7/04 (2006.01)
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15
Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09
Recombinant DNA-technology
11
DNA or RNA fragments; Modified forms thereof
113
Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
9
Enzymes, e.g. ligases (6.); Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating, or purifying enzymes
14
Hydrolases (3.)
16
acting on ester bonds (3.1)
22
Ribonucleases
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15
Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09
Recombinant DNA-technology
10
Processes for the isolation, preparation or purification of DNA or RNA
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15
Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09
Recombinant DNA-technology
63
Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
79
Vectors or expression systems specially adapted for eukaryotic hosts
85
for animal cells
86
Viral vectors
C CHEMISTRY; METALLURGY
12
BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
N
MICRO-ORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICRO-ORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
15
Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
09
Recombinant DNA-technology
87
Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
90
Stable introduction of foreign DNA into chromosome
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
K
PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
48
Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
A HUMAN NECESSITIES
61
MEDICAL OR VETERINARY SCIENCE; HYGIENE
P
SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
7
Drugs for disorders of the blood or the extracellular fluid
04
Antihaemorrhagics; Procoagulants; Haemostatatic agents; Antifibrinolytic agents
Applicants:
주식회사 툴젠 TOOLGEN INCORPORATED [KR/KR]; 서울시 금천구 가산디지털1로 219 1204호, 1205호, 1206호 No.1204, No.1205, No.1206 219, Gasan digital 1-ro Geumcheon-gu Seoul 08501, KR
Inventors:
김석중 KIM, Seokjoong; KR
송동우 SONG, Dong Woo; KR
이규준 LEE, Kyu Jun; KR
이정민 LEE, Jung-Min; KR
Agent:
이처영 LEE, Cheo Young; KR
장제환 CHANG, Je Hwan; KR
Priority Data:
62/564,70828.09.2017US
Title (EN) COMPOSITION FOR TREATMENT OF HEMOPHILIA, COMPRISING CRISPR/CAS SYSTEM HAVING COAGULATION FACTOR VIII GENE INVERSION CORRECTION POTENTIAL
(FR) COMPOSITION POUR LE TRAITEMENT DE L'HÉMOPHILIE, COMPRENANT UN SYSTÈME CRISPR/CAS AYANT UN POTENTIEL DE CORRECTION D'INVERSION DU GÈNE DU FACTEUR VIII DE COAGULATION
(KO) 혈액응고인자 VIII 유전자 역위 보정능의 유전자 가위 시스템으로 구성된 혈우병 치료용 조성물
Abstract:
(EN) The present invention relates to a CRISPR/Cas system having an inversion correction potential, which uses at least one guide RNA targeting a sequence region where two different homologs present on genomic introns are conjugated to each other in an inversion manner, and a Cas protein, and a CRISPR/Cas system of FVIII gene inversion correction potential that uses at least one guide RNA targeting an int22-1/3 homology or int22-1/2 homolog sequence region present on intron 22 of coagulation factor VIII (F8) gene and a Cas protein. A CRISPR/Cas system according to the present invention comprises a system which employs a small-size Cas9 and a guide RNA fitted thereto, thereby enabling all CRISPR/Cas instruments to be easily packaged in one AAV, which is impossible in conventional large-size Cas9. In addition, the CRISPR/Cas system can induce normal gene expression thanks to the inversion gene correction potential thereof and is excellent as a technology capable of effectively overcoming the difficult intracellular delivery of large-size gene mutation through gene editing. Particularly, the system can induce normal FVIII expression by restoring the inversion of FVIII gene and thus is useful for the treatment of hemophilia A.
(FR) La présente invention concerne un système CRISPR/Cas ayant un potentiel de correction d'inversion, qui utilise au moins un ARN guide ciblant une région de séquence où deux homologues différents présents sur des introns génomiques sont conjugués l'un à l'autre à la manière d'une inversion, et une protéine Cas, et un système CRISPR/Cas ayant un potentiel de correction d'inversion du gène du FVIII qui utilise au moins un ARN guide ciblant une région d'homologie int22-1/3 ou une région de séquence homologue int22-1/2 présente sur l'intron 22 du gène du facteur VIII (F8) de coagulation et une protéine Cas. Un système CRISPR/Cas selon la présente invention comprend un système qui utilise une Cas9 de petite taille et un ARN guide ajusté à celle-ci, ce qui permet ainsi d'empaqueter facilement tous les instruments CRISPR/Cas dans un AAV, ce qui est impossible dans les Cas9 classiques de grande taille. De plus, le système CRISPR/Cas peut induire une expression génique normale grâce au potentiel de correction d'inversion de gène de celui-ci et est excellent en tant que technologie capable de surmonter efficacement l'administration intracellulaire difficile d'une mutation de gène de grande taille par l'intermédiaire d'une édition de gène. En particulier, le système peut induire une expression de FVIII normale par restauration de l'inversion du gène de FVIII et est donc utile pour le traitement de l'hémophilie A.
(KO) 본 발명은 게놈 상의 인트론(intron)에 존재하는 서로 다른 두 상동체(homolog)가 역위(inversion)되어 접합된 서열 부위를 표적으로 하는 하나 이상의 가이드 RNA 및 Cas 단백질을 이용한 역위 보정능의 유전자 가위 시스템(CRISPR/Cas system), 및 혈액응고인자 VIII(F8) 유전자 내 22번 인트론(intron)에 존재하는 int22-1/3 상동체 또는 int22-1/2 상동체 서열 부위를 표적으로 하는 하나 이상의 가이드 RNA 및 Cas 단백질을 이용한 FVIII 유전자 역위 보정능의 유전자 가위 시스템(CRISPR/Cas system)에 관한 것이다. 본 발명에 따른 유전자 가위 시스템(CRISPR/Cas system)은 작은 사이즈의 Cas9 및 그에 맞는 가이드 RNA를 사용함으로써 기존의 큰 사이즈 Cas9에서는 불가능 했었던 하나의 AAV에 모든 유전자가위 도구를 용이하게 패키징할 수 있는 시스템으로 이루어져 있고, 또한 역위 유전자 보정능에 의하여 정상적인 유전자 발현을 유도할 수 있어, 세포 내 전달이 어려운 큰 사이즈의 유전자 변이를 유전자 교정을 통해 효율적으로 극복할 수 있는 기술로서의 탁월하다. 특히, FVIII 유전자의 역위를 복원시켜 정상적인 FVIII 발현을 유도할 수 있으므로, A형 혈우병의 치료에 유용하다.
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African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Office (AM, AZ, BY, KG, KZ, RU, TJ, TM)
European Patent Office (EPO) (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR)
African Intellectual Property Organization (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG)
Publication Language: Korean (KO)
Filing Language: Korean (KO)