JPWO2019222354A5 - - Google Patents

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JPWO2019222354A5
JPWO2019222354A5 JP2020563947A JP2020563947A JPWO2019222354A5 JP WO2019222354 A5 JPWO2019222354 A5 JP WO2019222354A5 JP 2020563947 A JP2020563947 A JP 2020563947A JP 2020563947 A JP2020563947 A JP 2020563947A JP WO2019222354 A5 JPWO2019222354 A5 JP WO2019222354A5
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viral vector
promoter
nucleic acid
interfering rna
rna
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JP2020563947A
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JP2021522836A (en
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Priority claimed from PCT/US2019/032423 external-priority patent/WO2019222354A1/en
Publication of JP2021522836A publication Critical patent/JP2021522836A/en
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Claims (20)

ウイルスベクターであって、それぞれが少なくとも17ヌクレオチドの長さの干渉リボ核酸(RNA)をコードする1以上のトランスジーンを含み、ここで、各干渉RNAは拡張リピート領域を含む内因性RNA転写物にアニーリングする部分を含み、且つ各干渉RNAの前記部分は前記拡張リピート領域と重ならない前記内因性RNA転写物のセグメントにアニーリングする、ウイルスベクター。 Viral vectors containing one or more transgenes, each encoding an interfering ribonucleic acid (RNA) of at least 17 nucleotides in length, where each interfering RNA is an endogenous RNA transcript containing an extended repeat region. A viral vector comprising an annealing moiety, wherein said moiety of each interfering RNA annealies to a segment of said endogenous RNA transcript that does not overlap with said extended repeat region. 前記内因性RNA転写物がヒトジストロフィアミオトニカプロテインキナーゼ(DMPK)をコードする、請求項1のウイルスベクター。 The viral vector of claim 1, wherein the endogenous RNA transcript encodes a human dystrophy myotonica protein kinase (DMPK). 前記拡張リピート領域が50以上のCUGトリヌクレオチドリピートを含む、請求項2のウイルスベクター。 The viral vector of claim 2, wherein the extended repeat region comprises 50 or more CUG trinucleotide repeats. 前記ベクターが、前記干渉RNAにアニーリングしないヒトDMPK RNA転写物をコードするトランスジーンをさらに含む、請求項2又は3に記載のウイルスベクター。 The viral vector of claim 2 or 3 , wherein the vector further comprises a transgene encoding a human DMPK RNA transcript that does not anneal to the interfering RNA. 前記ヒトDMPK RNA転写物が、前記干渉RNAに85%未満の相補性を有する、請求項4ウイルスベクターベクター。 The viral vector vector of claim 4 , wherein the human DMPK RNA transcript has less than 85% complementarity to the interfering RNA. 前記内因性RNA転写物が、配列番号1又は配列番号2の核酸配列に対して少なくとも85%の配列同一性を有する部分を含む、請求項2~5のいずれか1項に記載のウイルスベクター。 The viral vector according to any one of claims 2 to 5 , wherein the endogenous RNA transcript comprises a moiety having at least 85% sequence identity to the nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2. 前記各干渉RNAの部分が、
(a)ヒトDMPKのエクソン1~15のいずれか1つ内の
(b)ヒトDMPKのイントロン1~14のいずれか1つ内の、
(c)ヒトDMPK内のエクソン-イントロン境界を含む、又は
(d)ヒトDMPKの5'UTR又は3'UTR内の、
セグメントの核酸配列に少なくとも85%相補的な核酸配列を有する、請求項2~6のいずれか1項に記載のウイルスベクター。
The part of each interfering RNA is
(a) Within any one of exons 1 to 15 of human DMPK ,
(b) Within any one of the human DMPK introns 1-14,
(c) Includes or contains an exon-intron boundary within the human DMPK
(d) Within the 5'UTR or 3'UTR of the human DMPK,
The viral vector according to any one of claims 2 to 6 , which has a nucleic acid sequence that is at least 85% complementary to the nucleic acid sequence of the segment.
前記各干渉RNAの部分が、配列番号3~39のいずれか1つの核酸配列を有する内因性RNA転写物のセグメントにアニーリングする、請求項2~6のいずれか1項のウイルスベクター。 The viral vector according to any one of claims 2 to 6 , wherein the portion of each interfering RNA is annealed to a segment of an endogenous RNA transcript having the nucleic acid sequence of any one of SEQ ID NOs: 3 to 39. 前記干渉RNAが、配列番号3~161のいずれか1つの核酸配列に対して少なくとも85%の配列同一性を有する部分を含む、請求項2~8のいずれか1項に記載のウイルスベクター。 The viral vector according to any one of claims 2 to 8 , wherein the interfering RNA comprises a portion having at least 85% sequence identity to the nucleic acid sequence of any one of SEQ ID NOs: 3 to 161. 前記内因性RNA転写物が、ヒト染色体9オープンリーディングフレーム72(C9ORF72)及び拡張リピート領域を含む、請求項1のウイルスベクター。 The viral vector of claim 1, wherein the endogenous RNA transcript comprises a human chromosome 9 open reading frame 72 (C9ORF72) and an extended repeat region. 前記拡張リピート領域が、約25~約1600個のGGGGCCヘキサヌクレオチドリピートを含む、請求項10のウイルスベクター。 The viral vector of claim 10 , wherein the extended repeat region comprises from about 25 to about 1600 GGGGCC hexanucleotide repeats. 前記内因性RNA転写物が、配列番号163、165、又は166の核酸配列に対して少なくとも85%の配列同一性を有する部分を含む、請求項10又は11に記載のウイルスベクター。 The viral vector according to claim 10 or 11 , wherein the endogenous RNA transcript comprises a moiety having at least 85% sequence identity to the nucleic acid sequence of SEQ ID NO: 163, 165, or 166. 前記各干渉RNAの部分が、ヒトC9ORF72内のセグメントの核酸配列に対して少なくとも85%相補的な核酸配列を有する、請求項1012のいずれか1項に記載のウイルスベクター。 The viral vector according to any one of claims 10 to 12 , wherein each portion of the interfering RNA has a nucleic acid sequence that is at least 85% complementary to the nucleic acid sequence of the segment within human C9ORF72. 前記干渉RNAが、ショートインターフェアリングRNA(siRNA)、ショートヘアピンRNA(shRNA)、又はマイクロRNA(miRNA)であ任意に前記miRNAがU6 miRNAであり、任意に前記ウイルスベクターが
(a)成熟miRNAをコードするプライマリーmiRNA(pri-miRNA)転写物、又は
(b)成熟miRNAをコードするpre-miRNA転写物、
を含む、請求項1~13のいずれか1項に記載のウイルスベクター。
The interfering RNA is short interfering RNA (siRNA), short hairpin RNA (shRNA), or microRNA (miRNA) , optionally the miRNA is U6 miRNA, and optionally the virus vector.
(a) Primary miRNA (pri-miRNA) transcripts encoding mature miRNAs, or
(b) pre-miRNA transcripts encoding mature miRNAs,
The viral vector according to any one of claims 1 to 13 , which comprises .
前記干渉RNAが、筋細胞又はニューロンにおける干渉RNAの発現を誘導するプロモーターに動作可能に連結している、請求項1~14のいずれか1項に記載のウイルスベクター。 The viral vector according to any one of claims 1 to 14 , wherein the interfering RNA is operably linked to a promoter that induces expression of the interfering RNA in muscle cells or neurons. 前記プロモーターが、デスミンプロモーター、ホスホグリセリン酸キナーゼ(PGK)プロモーター、筋クレアチンキナーゼプロモーター、ミオシン軽鎖プロモーター、ミオシン重鎖プロモーター、心臓トロポニンCプロモーター、トロポニンIプロモーター、myoD遺伝子ファミリープロモーター、アクチンアルファプロモーター、アクチンベータプロモーター、アクチンガンマプロモーター、又はオキュラーペアード様ホメオドメイン3(PITX3)のイントロン1内のプロモーターである、請求項15のウイルスベクター。 The promoters are desmin promoter, phosphoglycerate kinase (PGK) promoter, muscle creatin kinase promoter, myosin light chain promoter, myosin heavy chain promoter, cardiac troponin C promoter, troponin I promoter, myoD gene family promoter, actin alpha promoter, actin. The viral vector of claim 15 , which is a beta promoter, an actin gamma promoter, or a promoter within Intron 1 of an ocular paired-like homeodomain 3 (PITX3). 前記ウイルスベクターが、アデノ随伴ウイルス(AAV)、アデノウイルス、レンチウイルス、レトロウイルス、ポックスウイルス、バキュロウイルス、単純ヘルペスウイルス、ワクシニアウイルス、及び合成ウイルスからなる群から選択され、任意に前記AAVがAAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAVrh10、又はAAVrh74セロタイプである、請求項1~16のいずれか1項に記載のウイルスベクター。 The virus vector is selected from the group consisting of adeno-associated virus (AAV), adenovirus, lentivirus, retrovirus, poxvirus, baculovirus, simple herpesvirus, vaccinia virus, and synthetic virus, and the AAV is optionally AAV1. , AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh10, or AAVrh74 cellotype, the virus vector according to any one of claims 1 to 16 . 前記ウイルスベクターが偽型AAVであ任意に前記偽型AAVがAAV2/8又はAAV2/9である、請求項17のウイルスベクター。 17. The viral vector of claim 17 , wherein the viral vector is pseudo-AAV, and optionally the pseudo-AAV is AAV2 / 8 or AAV2 / 9 . 干渉RNAをコードする又は含む核酸であって、前記干渉RNAは、配列番号3~161のいずれか1つの核酸配列に対して少なくとも85%の配列同一性を有する部分を含む、核酸。 A nucleic acid encoding or containing an interfering RNA, wherein the interfering RNA comprises a moiety having at least 85% sequence identity to any one of the nucleic acid sequences of SEQ ID NOs: 3 to 161. 筋強直性ジストロフィー又は筋萎縮性側索硬化症を有するヒト患者におけるスプライスオパシーの発生を減少させる又は治療する方法に使用するための、請求項1~18のいずれか1つのベクターを含む組成物であって前記方法は治療的に有効な量の請求項1~18のいずれか1つのベクター、又は請求項19核酸を含む組成物を前記患者に投与する工程を含む、組成物 A composition comprising the vector according to any one of claims 1 to 18 for use in a method for reducing or treating the occurrence of splice opacity in a human patient with myotonic dystrophy or myotonic lateral sclerosis . A composition comprising the step of administering to the patient a composition comprising a therapeutically effective amount of any one of the vectors of claims 1-18 , or the nucleic acid of claim 19 .
JP2020563947A 2018-05-15 2019-05-15 Compositions and methods for reducing splice opacity and treating RNA dominance disorders Pending JP2021522836A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201862671769P 2018-05-15 2018-05-15
US62/671,769 2018-05-15
PCT/US2019/032423 WO2019222354A1 (en) 2018-05-15 2019-05-15 Compositions and methods for reducing spliceopathy and treating rna dominance disorders

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JP2021522836A JP2021522836A (en) 2021-09-02
JPWO2019222354A5 true JPWO2019222354A5 (en) 2022-05-24

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US (1) US20210269825A1 (en)
EP (1) EP3793566A4 (en)
JP (1) JP2021522836A (en)
KR (1) KR20210010549A (en)
CN (1) CN112469421A (en)
AU (1) AU2019268346A1 (en)
BR (1) BR112020023298A2 (en)
CA (1) CA3098249A1 (en)
CL (1) CL2020002955A1 (en)
CO (1) CO2020015239A2 (en)
MA (1) MA51938B1 (en)
MX (1) MX2020012269A (en)
PH (1) PH12020551913A1 (en)
SG (1) SG11202011151VA (en)
WO (1) WO2019222354A1 (en)

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WO2023034870A2 (en) 2021-09-01 2023-03-09 Ionis Pharmaceuticals, Inc. Compounds and methods for reducing dmpk expression
WO2023196862A1 (en) * 2022-04-06 2023-10-12 Genzyme Corporation Targeted gene therapy for dm-1 myotonic dystrophy
WO2023220719A2 (en) * 2022-05-13 2023-11-16 University Of Washington Method for treatment of myotonic dystrophy combining protein expression and rna interference vector delivery with tissue detargeting
WO2024006770A1 (en) * 2022-06-27 2024-01-04 Astellas Gene Therapies, Inc. Compositions and methods for the treatment of myotonic dystrophies

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US5977333A (en) * 1992-02-06 1999-11-02 Massachusetts Institute Of Technology DNA sequence encoding the myotonic dystrophy gene and uses thereof
US20050042646A1 (en) * 2002-08-05 2005-02-24 Davidson Beverly L. RNA interference suppresion of neurodegenerative diseases and methods of use thereof
BR112017013573A2 (en) * 2014-12-24 2018-03-06 Uniqure Ip Bv double stranded rna, dna sequence, expression cassette, gene therapy vector, and host cell.
US11260073B2 (en) * 2015-11-02 2022-03-01 Ionis Pharmaceuticals, Inc. Compounds and methods for modulating C90RF72
SG10202102997UA (en) * 2016-09-30 2021-04-29 Regeneron Pharma Non-human animals having a hexanucleotide repeat expansion in a c9orf72 locus

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