JPWO2021168362A5 - - Google Patents

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JPWO2021168362A5
JPWO2021168362A5 JP2022549865A JP2022549865A JPWO2021168362A5 JP WO2021168362 A5 JPWO2021168362 A5 JP WO2021168362A5 JP 2022549865 A JP2022549865 A JP 2022549865A JP 2022549865 A JP2022549865 A JP 2022549865A JP WO2021168362 A5 JPWO2021168362 A5 JP WO2021168362A5
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Priority claimed from PCT/US2021/018919 external-priority patent/WO2021168362A1/en
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配列番号９６の組換えＡＡＶベクター。 Recombinant AAV vector of SEQ ID NO: 96. 配列番号１０５の組換えＡＡＶベクター。 Recombinant AAV vector of SEQ ID NO: 105. ５’から３’の順に、
配列番号９７の５’ＩＴＲ配列と、
配列番号９８のＣＭＶ初期エンハンサーエレメント、配列番号９９のニワトリベータアクチン遺伝子配列、および配列番号１００のキメライントロンを含む、ＣＡＧプロモーターと、
ＯＴＯＦ ｃＤＮＡのエクソン１から２１（まで）を含む、５’ＯＴＯＦコーディング領域と、
配列番号１０２のＳＤイントロン配列と、
配列番号１０３のＡＫ組換え誘導性配列と、
配列番号１０４の３’ＩＴＲ配列と
を含む、組換えＡＡＶベクター。 In order from 5' to 3',
5'ITR sequence of SEQ ID NO: 97,
a CAG promoter comprising a CMV early enhancer element of SEQ ID NO: 98, a chicken beta actin gene sequence of SEQ ID NO: 99, and a chimeric intron of SEQ ID NO: 100;
a 5'OTOF coding region, including exons 1 to 21 of the OTOF cDNA;
SD intron sequence of SEQ ID NO: 102,
AK recombination-inducing sequence of SEQ ID NO: 103;
A recombinant AAV vector comprising the 3'ITR sequence of SEQ ID NO: 104. 前記５’ＯＴＯＦコーディング領域が、配列番号１０１である、請求項３に記載の組換えＡＡＶベクター。 4. The recombinant AAV vector of claim 3, wherein the 5' OTOF coding region is SEQ ID NO: 101. 前記５’ＯＴＯＦコーディング領域が、配列番号１０１に対して少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％、少なくとも９９％、少なくとも９９．５％、または少なくとも９９．９％同一であり、配列番号１０１によってコードされるものと同じアミノ酸配列をコードする、請求項３または４に記載の組換えＡＡＶベクター。 the 5'OTOF coding region is at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95% of SEQ ID NO: 101; 101 is at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% identical and encodes the same amino acid sequence as encoded by SEQ ID NO: 101. 4. The recombinant AAV vector according to 3 or 4. ５’から３’の順に、
配列番号９７の５’ＩＴＲ配列と、
配列番号１０３のＡＫ組換え誘導性配列と、
配列番号１０６のＳＡイントロン配列と、
ＯＴＯＦ ｃＤＮＡのエクソン２２からエクソン４８（まで）を含む、３’ＯＴＯＦコーディング領域と、
配列番号１０８のｂｇＨポリＡ配列と、
配列番号１０４の３’ＩＴＲ配列と
を含む、組換えＡＡＶベクター。 In order from 5' to 3',
5'ITR sequence of SEQ ID NO: 97,
AK recombination-inducing sequence of SEQ ID NO: 103;
SA intron sequence of SEQ ID NO: 106,
A 3′ OTOF coding region, including exon 22 to exon 48 (up to) of the OTOF cDNA;
bgH polyA sequence of SEQ ID NO: 108,
A recombinant AAV vector comprising the 3'ITR sequence of SEQ ID NO: 104. 前記３’ＯＴＯＦコーディング領域が、配列番号１０７である、請求項６に記載の組換えＡＡＶベクター。 7. The recombinant AAV vector of claim 6, wherein the 3' OTOF coding region is SEQ ID NO: 107. 前記３’ＯＴＯＦコーディング領域が、配列番号１０７に対して少なくとも７０％、少なくとも８０％、少なくとも８５％、少なくとも９０％、少なくとも９１％、少なくとも９２％、少なくとも９３％、少なくとも９４％、少なくとも９５％、少なくとも９６％、少なくとも９７％、少なくとも９８％、少なくとも９９％、少なくとも９９．５％、または少なくとも９９．９％同一であり、配列番号１０７によってコードされるものと同じアミノ酸配列をコードする、請求項６または７に記載の組換えＡＡＶベクター。 the 3′ OTOF coding region is at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95% relative to SEQ ID NO: 107; Claims that are at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% identical and encode the same amino acid sequence as encoded by SEQ ID NO: 107. 7. The recombinant AAV vector according to 6 or 7. Ａｎｃ８０キャプシドによってキャプシド封入された請求項１～４及び６～７のいずれか一項に記載の組換えＡＡＶベクターを含み、場合により前記Ａｎｃ８０カプシドが配列番号１０９のポリペプチドを含む、組換えＡＡＶ粒子（ｒＡＡＶ粒子）。 Recombinant AAV comprising a recombinant AAV vector according to any one of claims 1 to 4 and 6 to 7 encapsidated by an Anc80 capsid , optionally said Anc80 capsid comprising the polypeptide of SEQ ID NO: 109. particles (rAAV particles). 請求項１に記載の組換えＡＡＶベクターを含む第１のｒＡＡＶ粒子と、請求項２に記載の組換えＡＡＶベクターを含む第２のｒＡＡＶ粒子とを含む、組成物。 A composition comprising a first rAAV particle comprising the recombinant AAV vector of claim 1 and a second rAAV particle comprising the recombinant AAV vector of claim 2. 請求項３から４のいずれか一項に記載の組換えＡＡＶベクターを含む第１のｒＡＡＶ粒子と、請求項６から７のいずれか一項に記載の組換えＡＡＶベクターを含む第２のｒＡＡＶ粒子とを含む、組成物。 A first rAAV particle comprising a recombinant AAV vector according to any one of claims 3 to 4 and a second rAAV particle comprising a recombinant AAV vector according to any one of claims 6 to 7 . A composition comprising: 前記第１および第２のｒＡＡＶ粒子が、それぞれ独立して、Ａｎｃ８０キャプシドによってキャプシド封入されており、、場合により前記Ａｎｃ８０カプシドが配列番号１０９のポリペプチドを含む、請求項１０に記載の組成物。 11. The composition of claim 10, wherein the first and second rAAV particles are each independently encapsidated by an Anc80 capsid , and optionally the Anc80 capsid comprises a polypeptide of SEQ ID NO: 109 . . 前記組成物がヒト細胞に導入されると、請求項１および２に記載の組換えＡＡＶベクターが、コンカテマー形成または互いの相同組換えを起こし、それによって、前記細胞内で全長オトフェリンタンパク質をコードする組換えられた核酸を形成する、請求項１０に記載の組成物。 When the composition is introduced into human cells, the recombinant AAV vectors according to claims 1 and 2 undergo concatemer formation or homologous recombination with each other, thereby encoding the full-length otoferlin protein in the cells. 11. The composition of claim 10 , wherein the composition forms a recombinant nucleic acid. 前記組成物がヒト細胞に導入されると、請求項３から４のいずれか一項に記載の組換えＡＡＶベクターおよび請求項６から７のいずれか一項に記載の組換えＡＡＶベクターが、コンカテマー形成または互いの相同組換えを起こし、それによって、前記細胞内で全長オトフェリンタンパク質をコードする組換えられた核酸を形成する、請求項１１に記載の組成物。 When the composition is introduced into human cells, the recombinant AAV vector according to any one of claims 3 to 4 and the recombinant AAV vector according to any one of claims 6 to 7 are transformed into concatemers. 12. The composition of claim 11 , wherein the composition undergoes homologous recombination with each other, thereby forming a recombinant nucleic acid encoding a full-length otoferlin protein within said cell. 少なくとも１つの薬学的に許容される賦形剤をさらに含む、請求項１０に記載の組成物。 11. The composition of claim 10 , further comprising at least one pharmaceutically acceptable excipient. 治療有効量を、哺乳動物の蝸牛に導入するための組成物であり、ここで場合により前記哺乳動物が人である、請求項１０に記載の組成物。 11. The composition of claim 10, wherein the composition is for introducing a therapeutically effective amount into the cochlea of a mammal, wherein said mammal is optionally a human. 前記哺乳動物が、欠損したオトフェリン遺伝子を有するとして以前に特定されている、請求項１６に記載の組成物。。 17. The composition of claim 16 , wherein the mammal has been previously identified as having a defective otoferlin gene . . 哺乳動物細胞において全長オトフェリンタンパク質の発現を増加させるための組成物であって、場合により前記哺乳動物細胞が内毛細胞である、請求項１０に記載の組成物。 11. A composition according to claim 10, for increasing expression of full-length otoferlin protein in a mammalian cell , optionally said mammalian cell being an inner hair cell. 前記哺乳動物細胞が、ヒト細胞であり、場合により当該哺乳動物細胞が欠損オトフェリン遺伝子を有することが依然に判定されている、請求項１８に記載の組成物。。 19. The composition of claim 18 , wherein the mammalian cell is a human cell, and where the mammalian cell has optionally been previously determined to have a defective otoferlin gene . . 哺乳動物の蝸牛の内有毛細胞における全長オトフェリンタンパク質の発現を増加させるための組成物であって、治療有効量を、前記哺乳動物の前記蝸牛に導入するためであり、当該哺乳動物細胞が欠損オトフェリン遺伝子を有することが依然に判定されており、場合により前記哺乳動物がヒトである、請求項１０に記載の組成物。 A composition for increasing the expression of full length otoferrin protein in the inner hair cells of the cochlea of a mammal, the composition comprising: introducing a therapeutically effective amount into the cochlea of the mammal; 11. The composition of claim 10, wherein the mammal has been determined to have a defective otoferlin gene and optionally is a human . 欠損したオトフェリン遺伝子を有するとして特定された対象において、無症状性感音性聴力喪失を治療するための組成物であって、治療有効量を、前記対象の蝸牛に投与するためであり、ここで場合により前記対象が人である、請求項１０に記載の組成物。 A composition for treating subclinical sensorineural hearing loss in a subject identified as having a defective otoferlin gene, the composition comprising: administering a therapeutically effective amount to the cochlea of said subject ; 11. The composition according to claim 10, wherein the subject is a human. 前記投与するステップの前に、前記対象が欠損したオトフェリン遺伝子を有することが判定される、請求項２１に記載の組成物。。 22. The composition of claim 21, wherein , prior to said administering step, it is determined that said subject has a defective otoferlin gene. . 前記組成物が、マイクロカテーテルを使用して、前記蝸牛に投与される、請求項２０に記載の組成物。 21. The composition of claim 20, wherein the composition is administered to the cochlea using a microcatheter. 前記マイクロカテーテルが、外耳道を介して中耳腔に進入し、前記マイクロカテーテルの端部をＲＷＭと接触させることができる形状をしており、そして場合により前記マイクロカテーテルの遠位端が、１０～１，０００ミクロンの直径を有する少なくとも１つのマイクロニードルから構成される、請求項２３に記載の組成物。 The microcatheter is configured to enter the middle ear cavity via the external auditory canal and contact the end of the microcatheter with the RWM , and optionally the distal end of the microcatheter is configured to 24. The composition of claim 23 , comprised of at least one microneedle having a diameter of 1,000 microns . 前記組成物が、ニードルを含むデバイスを使用して、前記蝸牛に投与され、ここで場合により前記針が湾曲部分および角度のついた先端部を含む、請求項２０に記載の組成物。 21. The composition of claim 20, wherein the composition is administered to the cochlea using a device that includes a needle , where the needle optionally includes a curved portion and an angled tip . 請求項１０に記載の組成物を含む、キット。 A kit comprising the composition of claim 10 . 前記組成物が、デバイスに事前充填されており、場合により前記デバイスがマイクロカテーテルである、請求項２６に記載のキット。 27. A kit according to claim 26 , wherein the composition is preloaded into a device, optionally the device being a microcatheter . 前記マイクロカテーテルが、外耳道を介して中耳腔に進入し、前記マイクロカテーテルの端部をＲＷＭと接触させることができる形状をしており、場合により前記マイクロカテーテルの遠位端が、１０～１，０００ミクロンの直径を有する少なくとも１つのマイクロニードルから構成される、請求項２７に記載のキット。 The microcatheter is shaped to enter the middle ear cavity via the external auditory canal and bring the end of the microcatheter into contact with the RWM, and optionally the distal end of the microcatheter has a diameter of 10 to 1 28. The kit of claim 27, comprising at least one microneedle having a diameter of ,000 microns . デバイスをさらに含み、場合によりここで前記デバイスが図８２～８７のいずれか１つに記載されているデバイスであり、ここで前記デバイスが湾曲部分および角度のついた先端部を含むニードルを含む、請求項２６に記載のキット。 further comprising a device, optionally wherein the device is the device described in any one of FIGS. 82-87, wherein the device includes a needle including a curved portion and an angled tip. , the kit according to claim 26 . 以下の：below:
ａ）配列番号９６の核酸配列を含む第１のｒＡＡＶベクター；およびa) a first rAAV vector comprising the nucleic acid sequence of SEQ ID NO: 96; and
ｂ）配列番号１０５の核酸配列を含む第２のｒＡＡＶベクターb) a second rAAV vector comprising the nucleic acid sequence of SEQ ID NO: 105
を含む、複数の組換えアデノ随伴ウイルス（ｒＡＡＶ）ベクター。A plurality of recombinant adeno-associated virus (rAAV) vectors, including: 第１および第２のｒＡＡＶベクターが、それぞれＡＡＶカプシドによって封入されている、請求項３０に記載の複数のｒＡＡＶベクター。31. The plurality of rAAV vectors of claim 30, wherein the first and second rAAV vectors are each encapsulated by an AAV capsid. 第１のｒＡＡＶベクターを封入するＡＡＶカプシドが、ＡＡＶ１、ＡＡＶ２、ＡＡＶ３、ＡＡＶ４、ＡＡＶ５、ＡＡＶ６、ＡＡＶ７、ＡＡＶ８、ＡＡＶ９、ＡＡＶｒｈ８、ＡＡＶｒｈ１０、ＡＡＶｒｈ３９、ＡＡＶｒｈ４３、またはＡｎｃ８０のいずれか１つから選択される血清型である、請求項３０に記載の複数のｒＡＡＶベクター。The AAV capsid encapsulating the first rAAV vector is a serum selected from any one of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, AAVrh39, AAVrh43, or Anc80. 31. The plurality of rAAV vectors of claim 30, wherein the rAAV vectors are of the type. 第２のｒＡＡＶベクターを封入するＡＡＶカプシドが、ＡＡＶ１、ＡＡＶ２、ＡＡＶ３、ＡＡＶ４、ＡＡＶ５、ＡＡＶ６、ＡＡＶ７、ＡＡＶ８、ＡＡＶ９、ＡＡＶｒｈ８、ＡＡＶｒｈ１０、ＡＡＶｒｈ３９、ＡＡＶｒｈ４３、またはＡｎｃ８０のいずれか１つから選択される血清型である、請求項３０に記載の複数のｒＡＡＶベクター。The AAV capsid encapsulating the second rAAV vector is a serum selected from any one of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, AAVrh39, AAVrh43, or Anc80. 31. The plurality of rAAV vectors of claim 30, wherein the rAAV vectors are of the type. 第１のｒＡＡＶベクターがＡｎｃ８０カプシドによって封入され、第２のｒＡＡＶベクターがＡｎｃ８０カプシドによって封入され、任意選択で、Ａｎｃ８０カプシドが配列番号１０９のポリペプチド配列を含む、請求項３０に記載の複数のｒＡＡＶベクター。31. The plurality of rAAVs of claim 30, wherein the first rAAV vector is encapsulated by an Anc80 capsid, the second rAAV vector is encapsulated by an Anc80 capsid, and optionally the Anc80 capsid comprises a polypeptide sequence of SEQ ID NO: 109. vector. 請求項３０～３４のいずれか１項に記載の複数のｒＡＡＶベクターを含む組成物であって、当該組成物がさらに１つ以上の薬学的に許容される担体、希釈剤、または賦形剤を含み、任意選択で、当該組成物が蝸牛内投与のために製剤化される、組成物。35. A composition comprising a plurality of rAAV vectors according to any one of claims 30-34, wherein the composition further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients. Optionally, the composition is formulated for intracochlear administration. 組成物が合成ペリリンパ溶液を含むように製剤化される、請求項３０～３４のいずれか１項に記載の組成物。35. A composition according to any one of claims 30 to 34, wherein the composition is formulated to include a synthetic perilymph solution. 哺乳動物細胞において組換え完全長オトフェリンタンパク質を発現させるための、複数の組換えアデノ随伴ウイルス（ｒＡＡＶ）ベクターを含む組成物あって、複数のｒＡＡＶベクターが以下の：A composition comprising a plurality of recombinant adeno-associated virus (rAAV) vectors for expressing recombinant full-length otoferlin protein in mammalian cells, wherein the plurality of rAAV vectors are:
ａ）配列番号９６の核酸配列を含む 第１のｒＡＡＶベクター；およびa) a first rAAV vector comprising the nucleic acid sequence of SEQ ID NO: 96; and
ｂ）配列番号１０５の核酸配列を含む第二のｒＡＡＶベクター；b) a second rAAV vector comprising the nucleic acid sequence of SEQ ID NO: 105;
を含み、ここで、前記哺乳動物細胞は、オトフェリンの発現の減少、発現の欠如または機能障害を有する、前記組成物。wherein said mammalian cell has reduced expression, lack of expression or impaired function of otoferlin. 前記哺乳動物細胞が内毛細胞であり、任意選択で、前記哺乳動物細胞がヒト細胞であり、任意選択で、前記哺乳動物細胞が欠損オトフェリン遺伝子を含む、請求項３７に記載の組成物。38. The composition of claim 37, wherein the mammalian cell is an inner hair cell, optionally the mammalian cell is a human cell, and optionally the mammalian cell comprises a defective otoferlin gene. オトフェリン関連難聴を有する被験体における難聴を治療するための、複数のｒＡＡＶベクターを含む組成物であって、複数の組換えアデノ随伴ウイルス（ｒＡＡＶ）ベクターが以下の：A composition comprising a plurality of rAAV vectors for treating hearing loss in a subject with otoferlin-associated hearing loss, wherein the plurality of recombinant adeno-associated virus (rAAV) vectors are:
ａ）a) 配列番号９６の核酸配列を含む 第１のｒＡＡＶベクター；およびa first rAAV vector comprising the nucleic acid sequence of SEQ ID NO: 96; and
ｂ）b) 配列番号１０５の核酸配列を含む、第二のｒＡＡＶベクター；a second rAAV vector comprising the nucleic acid sequence of SEQ ID NO: 105;
を含み、ここで、被験体がオトフェリンの発現低下、発現欠如、または機能不全を有し、任意選択で、被験体がヒトである、前記組成物。wherein the subject has reduced expression, lack of expression, or dysfunction of otoferlin, and optionally the subject is human. 第１および第２のｒＡＡＶベクターがそれぞれＡＡＶカプシドによって封入されている、請求項３７～３９のいずれか１項に記載の組成物。A composition according to any one of claims 37 to 39, wherein the first and second rAAV vectors are each encapsulated by an AAV capsid. 第１のｒＡＡＶベクターを封入するＡＡＶカプシドが、血清型ＡＡＶ１、ＡＡＶ２、ＡＡＶ３、ＡＡＶ４、ＡＡＶ５、ＡＡＶ６、ＡＡＶ７、ＡＡＶ８、ＡＡＶ９、ＡＡＶｒｈ８、ＡＡＶｒｈ１０、ＡＡＶｒｈ３９、ＡＡＶｒｈ４３、またはＡｎｃ８０である、請求項４０に記載の組成物。41. The AAV capsid encapsulating the first rAAV vector is of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, AAVrh39, AAVrh43, or Anc80. Composition of. 第２のｒＡＡＶベクターを封入するＡＡＶカプシドが、血清型ＡＡＶ１、ＡＡＶ２、ＡＡＶ３、ＡＡＶ４、ＡＡＶ５、ＡＡＶ６、ＡＡＶ７、ＡＡＶ８、ＡＡＶ９、ＡＡＶｒｈ８、ＡＡＶｒｈ１０、ＡＡＶｒｈ３９、ＡＡＶｒｈ４３、またはＡｎｃ８０である、請求項４０に記載の組成物。41. The AAV capsid encapsulating the second rAAV vector is of serotype AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, AAVrh39, AAVrh43, or Anc80. Composition of. 第１のｒＡＡＶベクターがＡｎｃ８０カプシドによって封入され、第２のｒＡＡＶベクターがＡｎｃ８０カプシドによって封入され、任意選択で、Ａｎｃ８０カプシドが配列番号１０９のポリペプチド配列を含む、請求項３７～３９のいずれか一項に記載の組成物。Any one of claims 37 to 39, wherein the first rAAV vector is encapsulated by an Anc80 capsid, the second rAAV vector is encapsulated by an Anc80 capsid, and optionally the Anc80 capsid comprises the polypeptide sequence of SEQ ID NO: 109. The composition described in Section. 複数のｒＡＡＶベクターが単回用量として投与されるか、または複数のｒＡＡＶベクターが２回以上の用量として投与される、請求項３７～３９のいずれか１項に記載の使用。The use according to any one of claims 37 to 39, wherein the rAAV vectors are administered as a single dose or the rAAV vectors are administered as two or more doses. 以下の：below:
ａ）５’から３’の順に以下のものを含む第１のｒＡＡＶベクター：a) A first rAAV vector comprising in 5' to 3' order:
（ｉ）配列番号９７の５’ＩＴＲ配列；(i) 5'ITR sequence of SEQ ID NO: 97;
（ｉｉ）ＣＡＧプロモーター；(ii) CAG promoter;
（ｉｉｉ）ＯＴＯＦ(iii) OTOF ｃＤＮＡのエクソン１～２１（まで）を含む５’ＯＴＯＦコード領域;5' OTOF coding region including exons 1 to 21 of the cDNA;
（ｉｖ）配列番号１０２のＳＤイントロン配列;(iv) SD intron sequence of SEQ ID NO: 102;
（ｖ）配列番号１０３のＡＫ組換え配列；および(v) the AK recombination sequence of SEQ ID NO: 103; and
（ｖｉ）配列番号１０４の３’ＩＴＲ配列；並びに(vi) 3'ITR sequence of SEQ ID NO: 104; and
ｂ）５’から３’の順序で、以下のものを含む第２のｒＡＡＶベクター：b) A second rAAV vector comprising, in 5' to 3' order:
（ｉ）配列番号９７の５’ＩＴＲ配列(i) 5'ITR sequence of SEQ ID NO: 97
（ｉｉ）配列番号１０３のＡＫ組換え配列(ii) AK recombination sequence of SEQ ID NO: 103
（ｉｉｉ）配列番号１０６のＳＡイントロン配列(iii) SA intron sequence of SEQ ID NO: 106
（ｉｖ）ＯＴＯＦｃＤＮＡのエクソン２２～エクソン４８（まで）を含む３’ＯＴＯＦコード領域(iv) 3' OTOF coding region including exon 22 to exon 48 (up to) of OTOF cDNA
（ｖ）ポリＡ配列；および(v) a polyA sequence; and
（ｖｉ）配列番号１０４の３’ＩＴＲ配列。(vi) 3'ITR sequence of SEQ ID NO: 104.
を含む、複数の組換えアデノ随伴（ｒＡＡＶ）ベクター。A plurality of recombinant adeno-associated (rAAV) vectors, including: 請求項４５に記載の複数のｒＡＡＶベクターと、１つまたは複数の薬学的に許容される担体、希釈剤、または賦形剤とを含む、組成物。46. A composition comprising a plurality of rAAV vectors of claim 45 and one or more pharmaceutically acceptable carriers, diluents, or excipients. Ａｎｃ８０カプシドにより封入された第１のｒＡＡＶベクターと、Ａｎｃ８０カプシドにより封入された第２のｒＡＡＶベクターとを含む組成物であって、以下の：A composition comprising a first rAAV vector encapsulated by an Anc80 capsid and a second rAAV vector encapsulated by an Anc80 capsid, the composition comprising:
ａ）第１のｒＡＡＶベクターは、５’から３’の順に、以下のものを含み：a) The first rAAV vector comprises, in 5' to 3' order:
（ｉ）配列番号９７の５’ＩＴＲ配列、(i) 5'ITR sequence of SEQ ID NO: 97,
（ｉｉ）ＣＡＧプロモーター、(ii) CAG promoter,
（ｉｉｉ）ＯＴＯＦ(iii) OTOF ｃＤＮＡのエクソン１～エクソン２１（まで）を含む５’ＯＴＯＦコード領域、5' OTOF coding region including exon 1 to exon 21 (up to) of the cDNA,
（ｉｖ）配列番号１０２のＳＤイントロン配列(iv) SD intron sequence of SEQ ID NO: 102
（ｖ）配列番号１０３のＡＫ組換え配列、および(v) AK recombination sequence of SEQ ID NO: 103, and
（ｖｉ）配列番号１０４の３’ＩＴＲ配列；そして(vi) the 3'ITR sequence of SEQ ID NO: 104; and
ｂ）第２のｒＡＡＶベクターは、５’から３’の順に、以下のものを含みる：b) The second rAAV vector contains, in 5' to 3' order:
（ｉ）(i) 配列番号９７の５’ＩＴＲ配列、5'ITR sequence of SEQ ID NO: 97,
（ｉｉ）配列番号１０３のＡＫ組換え配列、(ii) AK recombination sequence of SEQ ID NO: 103,
（ｉｉｉ）配列番号１０６のＳＡイントロン配列、(iii) SA intron sequence of SEQ ID NO: 106,
（ｉｖ）ＯＴＯＦ(iv) OTOF ｃＤＮＡのエクソン２２～エクソン４８（まで）を含む３’ＯＴＯＦコード領域、3' OTOF coding region including exon 22 to exon 48 (up to) of the cDNA,
（ｖ）ポリＡ配列、および(v) a polyA sequence, and
（ｖｉ）配列番号１０４の３’ＩＴＲ配列；(vi) 3'ITR sequence of SEQ ID NO: 104;
ここで、組成物は、１つ以上の薬学的に受容可能な担体、希釈剤、または賦形剤をさらに含む、前記組成物。wherein the composition further comprises one or more pharmaceutically acceptable carriers, diluents, or excipients. 以下の：below:
（ｉ）ＣＡＧプロモーターが、配列番号９８のＣＭＶ初期エンハンサーエレメント、配列番号９９のニワトリβアクチン遺伝子配列、および配列番号１００のキメライントロンを含み；および／または(i) the CAG promoter comprises a CMV early enhancer element of SEQ ID NO: 98, a chicken β-actin gene sequence of SEQ ID NO: 99, and a chimeric intron of SEQ ID NO: 100; and/or
（ｉｉ）ポリＡは、配列番号１０８の配列を有するｂＧＨポリＡである、(ii) polyA is bGH polyA having the sequence SEQ ID NO: 108;
複数のｒＡＡＶまたは請求項４５～４７のいずれか１項に記載の組成物。A plurality of rAAVs or a composition according to any one of claims 45-47. ５’ＯＴＯＦコード領域が配列番号１０１と少なくとも８０％同一であり、配列番号１０１によってコードされるのと同じアミノ酸配列をコードし、任意選択で、５’ＯＴＯＦコード領域が配列番号１０１を含む、請求項４５に記載の複数のｒＡＡＶまたは請求項４６又は４７に記載の組成物。101, wherein the 5'OTOF coding region is at least 80% identical to SEQ ID NO: 101, encodes the same amino acid sequence as encoded by SEQ ID NO: 101, and optionally, the 5'OTOF coding region comprises SEQ ID NO: 101. 48. A plurality of rAAVs according to claim 45 or a composition according to claim 46 or 47. ３’ＯＴＯＦコード領域が配列番号１０７と少なくとも８０％同一であり、配列番号１０７によってコードされるのと同じアミノ酸配列をコードし、任意選択で、３’ＯＴＯＦコード領域が配列番号１０７を含む、請求項４５に記載の複数のｒＡＡＶまたは請求項４６又は４７に記載の組成物。107, wherein the 3'OTOF coding region is at least 80% identical to SEQ ID NO: 107, encodes the same amino acid sequence as encoded by SEQ ID NO: 107, and optionally, the 3'OTOF coding region comprises SEQ ID NO: 107. 48. A plurality of rAAVs according to claim 45 or a composition according to claim 46 or 47. 第１のｒＡＡＶベクターが配列番号９６の核酸配列を含み；そして第２のｒＡＡＶベクターが配列番号１０５の核酸配列を含む、請求項４５に記載の複数のｒＡＡＶまたは請求項４６又は４７に記載の組成物。The plurality of rAAVs of claim 45 or the composition of claim 46 or 47, wherein the first rAAV vector comprises the nucleic acid sequence of SEQ ID NO: 96; and the second rAAV vector comprises the nucleic acid sequence of SEQ ID NO: 105. thing. 第１のｒＡＡＶベクターを封入するＡｎｃ８０カプシドが、配列番号１０９に対して少なくとも８５％の配列同一性を有するポリペプチドを含み；そして第２のｒＡＡＶベクターを封入するＡｎｃ８０カプシドが、配列番号１０９に対して少なくとも８５％の配列同一性を有するポリペプチドを含む、請求項４６～４７のいずれか１項に記載の組成物。An Anc80 capsid enclosing a first rAAV vector comprises a polypeptide having at least 85% sequence identity to SEQ ID NO: 109; and an Anc80 capsid enclosing a second rAAV vector comprises a polypeptide having at least 85% sequence identity to SEQ ID NO: 48. A composition according to any one of claims 46 to 47, comprising a polypeptide having at least 85% sequence identity. 前記組成物が蝸牛内投与のために製剤化され、任意選択で、該組成物が合成ペリリンパ溶液を含む、said composition is formulated for intracochlear administration, optionally said composition comprising a synthetic perilymph solution; 請求項４６～４７のいずれか１項に記載の組成物。A composition according to any one of claims 46 to 47.
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