JPWO2021081236A5 - - Google Patents
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- JPWO2021081236A5 JPWO2021081236A5 JP2022523436A JP2022523436A JPWO2021081236A5 JP WO2021081236 A5 JPWO2021081236 A5 JP WO2021081236A5 JP 2022523436 A JP2022523436 A JP 2022523436A JP 2022523436 A JP2022523436 A JP 2022523436A JP WO2021081236 A5 JPWO2021081236 A5 JP WO2021081236A5
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- c9orf72
- nucleic acid
- vector
- pharmaceutical composition
- expression cassette
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本開示は、以下の実施例によりさらに例示されるが、これらの実施例は、さらなる限定として解釈されるべきではない。すべての図ならびに本出願全体を通して引用されるすべての参考文献、特許および公開特許出願、ならびに図面は、それらの全体で参照により本明細書中に明示的に組み入れられる。
本発明は、例えば以下の実施形態を包含する:
[1]C9ORF72タンパク質をコードする核酸配列であって、コドン最適化されている、上記核酸配列。
[2]前記コドン最適化された配列が、表2に示される配列から選択される、[1]に記載の核酸配列。
[3]配列番号14~52のいずれか1つから選択される核酸配列に対して少なくとも85%同一である、[1]に記載の核酸配列。
[4] プロモーター;および
[1]~[3]のいずれかに記載の核酸配列
を含む、導入遺伝子発現カセット。
[5] プロモーター;
[1]~[3]のいずれかに記載の核酸配列;
c9orf72センス転写産物特異的阻害剤;および
c9orf72アンチセンス転写産物特異的阻害剤
を含む、導入遺伝子発現カセット。
[6]c9orf72センス転写産物特異的阻害剤が、核酸、アプタマー、抗体、ペプチド、または小分子のうちのいずれかである、[5]に記載の導入遺伝子発現カセット。
[7]前記核酸が、一本鎖核酸または二本鎖核酸である、[6]に記載の導入遺伝子発現カセット。
[8]前記核酸がマイクロRNA(miRNA)である、[6]に記載の導入遺伝子発現カセット。
[9]前記センス転写産物阻害剤が、表4に示されるmiRNAから選択される、[5]に記載の導入遺伝子発現カセット。
[10]前記アンチセンス転写産物阻害剤が、表3に示されるmiRNAから選択される、[5]に記載の導入遺伝子発現カセット。
[11]2つの逆位末端反復(ITR)をさらに含む、[4]または[5]に記載の導入遺伝子発現カセット。
[12]最小調節エレメントをさらに含む、[4]または[5]に記載の導入遺伝子発現カセット。
[13]前記プロモーターが、ニューロンでの発現に対して特異的である、[4]または[5]に記載の導入遺伝子発現カセット。
[14]前記プロモーターが、ヒトシナプシン1(hSyn)プロモーターである、[13]に記載の導入遺伝子発現カセット。
[15]前記核酸がヒト核酸である、[4]または[5]に記載の導入遺伝子発現カセット。
[16][4]または[5]に記載の発現カセットを含む、核酸ベクター。
[17]前記ベクターがアデノ随伴ウイルス(AAV)ベクターである。[16]に記載のベクター。
[18]前記AAVベクターのカプシド配列の血清型およびITRの血清型が、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、およびAAV12からなる群より独立して選択される、[17]に記載のベクター。
[19]前記カプシド配列が突然変異体カプシド配列である、[27]に記載のベクター。
[20][16]~[19]のいずれかに記載のベクターを含む哺乳動物細胞。
[21]アデノ随伴ウイルスベクターへと、
プロモーター;
および[1]~[3]のいずれかに記載の少なくとも1種の核酸
を挿入するステップを含む、組み換えアデノ随伴ウイルス(rAAV)ベクターの作製方法。
[22]アデノ随伴ウイルスベクターへと、
プロモーター;
[1]~[3]のいずれかに記載の少なくとも1種の核酸;
c9orf72センス転写産物特異的阻害剤;および
c9orf72アンチセンス転写産物特異的阻害剤
を挿入するステップを含む、組み換えアデノ随伴ウイルス(rAAV)ベクターの作製方法。
[23]前記核酸がヒト核酸である、[21]または[22]に記載の方法。
[24]前記AAVベクターのカプシド配列の血清型およびITRの血清型が、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、およびAAV12からなる群より独立して選択される、[21]または[22]に記載の方法。
[25]前記カプシド配列が突然変異体カプシド配列である、[24]に記載の方法。
[26][16]~[19]のいずれかに記載のベクターを、それを必要とする被験体に投与し、それにより該被験体でのc9orf72関連疾患を治療するステップを含む、c9orf72関連疾患を治療する方法。
[27][16]~[19]のいずれかに記載のベクターを、それを必要とする被験体に投与し、それにより該被験体でのc9orf72関連疾患を治療するステップを含む、c9orf72関連疾患の進行を予防する方法。
[28]前記c9orf72関連疾患がc9orf72ヘキサヌクレオチド反復拡張に関連する疾患である、[26]または[27]に記載の方法。
[29]前記c9orf72関連疾患が神経変性疾患である、[26]または[27]に記載の方法。
[30]前記神経変性疾患が、筋萎縮性側索硬化症(ALS)、前頭側頭型認知症(FTD)、パーキンソン病、進行性核上まひ、運動失調、大脳皮質基底核症候群、ハンチントン病様症候群、クロイツフェルト・ヤコブ病およびアルツハイマー病からなる群より選択される、[29]に記載の方法。
[31]前記神経変性疾患が、筋萎縮性側索硬化症(ALS)および/または前頭側頭型認知症(FTD)である、[29]に記載の方法。
[32]前記ALSが、家族性ALSまたは孤発性ALSである、[31]に記載の方法。
[33]前記被験体が、c9orf72遺伝子中に1箇所以上の突然変異を有する、[26]または[27]に記載の方法。
[34]前記1箇所以上の突然変異が、1箇所以上のヘキサヌクレオチド反復拡張、1箇所以上のナンセンス突然変異および1箇所以上のフレームシフト突然変異から選択される、[33]に記載の方法。
[35]c9orf72の発現が阻害または抑制される、[26]または[27]に記載の方法。
[36]前記c9orf72が、野生型c9orf72、突然変異型c9orf72、または野生型c9orf72および突然変異型c9orf72の両方である、[35]に記載の方法。
[37]c9orf72の発現が、約10%~約100%阻害または抑制される、[35]に記載の方法。
[38][16]~[19]のいずれかに記載のベクターを含む組成物を細胞に投与するステップを含む、細胞でのc9orf72遺伝子の発現を阻害するための方法であって、該c9orf72遺伝子がヘキサヌクレオチド反復拡張を含む、上記方法。
[39]前記ヘキサヌクレオチド反復拡張が、センスおよびアンチセンスc9orf72反復RNAからまたはジペプチド反復から、C9ORF72タンパク質の機能喪失および/または毒性機能獲得を引き起こす、[38]に記載の方法。
[40]前記細胞が哺乳動物細胞である、[38]に記載の方法。
[41]前記哺乳動物細胞が運動ニューロンまたは星状膠細胞である、[40]に記載の方法。
[42]前記ベクターが、頭蓋内投与により投与される、[26]~[41]のいずれかに記載の方法。
[43]前記頭蓋内投与が、髄腔内または脳室内投与を含む、[42]に記載の方法。
[44][16]~[19]のいずれかに記載のベクターおよび使用説明書を含む、キット。
[45]前記ベクターの頭蓋内投与送達のためのデバイスをさらに含む、[44]に記載のキット。
The present disclosure is further illustrated by the following examples, which should not be construed as further limitations. All figures and all references, patents and published patent applications, and drawings cited throughout this application are hereby expressly incorporated by reference in their entirety.
The present invention includes, for example, the following embodiments:
[1] The above nucleic acid sequence that encodes the C9ORF72 protein and is codon-optimized.
[2] The nucleic acid sequence according to [1], wherein the codon-optimized sequence is selected from the sequences shown in Table 2.
[3] The nucleic acid sequence according to [1], which is at least 85% identical to a nucleic acid sequence selected from any one of SEQ ID NOs: 14 to 52.
[4] Promoter; and
Nucleic acid sequence according to any one of [1] to [3]
A transgene expression cassette containing.
[5] Promoter;
The nucleic acid sequence according to any one of [1] to [3];
c9orf72 sense transcript-specific inhibitor; and
c9orf72 antisense transcript-specific inhibitor
A transgene expression cassette containing.
[6] The transgene expression cassette according to [5], wherein the c9orf72 sense transcript-specific inhibitor is any one of a nucleic acid, an aptamer, an antibody, a peptide, or a small molecule.
[7] The transgene expression cassette according to [6], wherein the nucleic acid is a single-stranded nucleic acid or a double-stranded nucleic acid.
[8] The transgene expression cassette according to [6], wherein the nucleic acid is microRNA (miRNA).
[9] The transgene expression cassette according to [5], wherein the sense transcript inhibitor is selected from the miRNAs shown in Table 4.
[10] The transgene expression cassette according to [5], wherein the antisense transcript inhibitor is selected from the miRNAs shown in Table 3.
[11] The transgene expression cassette according to [4] or [5], further comprising two inverted terminal repeats (ITR).
[12] The transgene expression cassette according to [4] or [5], further comprising a minimal regulatory element.
[13] The transgene expression cassette according to [4] or [5], wherein the promoter is specific for expression in neurons.
[14] The transgene expression cassette according to [13], wherein the promoter is the human synapsin 1 (hSyn) promoter.
[15] The transgene expression cassette according to [4] or [5], wherein the nucleic acid is a human nucleic acid.
[16] A nucleic acid vector comprising the expression cassette according to [4] or [5].
[17] The vector is an adeno-associated virus (AAV) vector. Vector described in [16].
[18] The serotype of the capsid sequence of the AAV vector and the serotype of the ITR are independently from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAV12. The vector described in [17] is selected.
[19] The vector according to [27], wherein the capsid sequence is a mutant capsid sequence.
[20] A mammalian cell containing the vector according to any one of [16] to [19].
[21] To adeno-associated virus vector,
promoter;
and at least one kind of nucleic acid according to any one of [1] to [3]
A method for producing a recombinant adeno-associated virus (rAAV) vector, the method comprising the step of inserting a recombinant adeno-associated virus (rAAV) vector.
[22] To adeno-associated virus vector,
promoter;
At least one type of nucleic acid according to any one of [1] to [3];
c9orf72 sense transcript-specific inhibitor; and
c9orf72 antisense transcript-specific inhibitor
A method for producing a recombinant adeno-associated virus (rAAV) vector, the method comprising the step of inserting a recombinant adeno-associated virus (rAAV) vector.
[23] The method according to [21] or [22], wherein the nucleic acid is a human nucleic acid.
[24] The serotype of the capsid sequence of the AAV vector and the serotype of the ITR are independently from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAV12. The method described in [21] or [22] is selected.
[25] The method according to [24], wherein the capsid sequence is a mutant capsid sequence.
[26] A c9orf72-related disease, comprising the step of administering the vector according to any one of [16] to [19] to a subject in need thereof, thereby treating the c9orf72-related disease in the subject. How to treat.
[27] A c9orf72-related disease, comprising the step of administering the vector according to any one of [16] to [19] to a subject in need thereof, thereby treating the c9orf72-related disease in the subject. How to prevent the progression of
[28] The method according to [26] or [27], wherein the c9orf72-related disease is a disease associated with c9orf72 hexanucleotide repeat expansion.
[29] The method according to [26] or [27], wherein the c9orf72-related disease is a neurodegenerative disease.
[30] The neurodegenerative disease is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease, progressive supranuclear palsy, ataxia, corticobasal syndrome, Huntington's disease The method according to [29], wherein the method is selected from the group consisting of Creutzfeldt-like syndrome, Creutzfeldt-Jakob disease, and Alzheimer's disease.
[31] The method according to [29], wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD).
[32] The method according to [31], wherein the ALS is familial ALS or sporadic ALS.
[33] The method according to [26] or [27], wherein the subject has one or more mutations in the c9orf72 gene.
[34] The method according to [33], wherein the one or more mutations are selected from one or more hexanucleotide repeat expansions, one or more nonsense mutations, and one or more frameshift mutations.
[35] The method according to [26] or [27], wherein the expression of c9orf72 is inhibited or suppressed.
[36] The method according to [35], wherein the c9orf72 is wild type c9orf72, mutant c9orf72, or both wild type c9orf72 and mutant c9orf72.
[37] The method according to [35], wherein the expression of c9orf72 is inhibited or suppressed by about 10% to about 100%.
[38] A method for inhibiting expression of the c9orf72 gene in a cell, the method comprising administering to the cell a composition comprising the vector according to any one of [16] to [19]. comprises a hexanucleotide repeat expansion.
[39] The method according to [38], wherein the hexanucleotide repeat expansion causes loss of function and/or toxic gain of function of the C9ORF72 protein from sense and antisense c9orf72 repeat RNAs or from dipeptide repeats.
[40] The method according to [38], wherein the cell is a mammalian cell.
[41] The method according to [40], wherein the mammalian cell is a motor neuron or an astrocyte.
[42] The method according to any one of [26] to [41], wherein the vector is administered by intracranial administration.
[43] The method according to [42], wherein the intracranial administration includes intrathecal or intraventricular administration.
[44] A kit comprising the vector according to any one of [16] to [19] and instructions for use.
[45] The kit according to [44], further comprising a device for intracranial administration delivery of the vector.
Claims (45)
請求項1~3のいずれか1項に記載の核酸配列
を含む、導入遺伝子発現カセット。 A transgene expression cassette comprising: a promoter; and a nucleic acid sequence according to any one of claims 1 to 3.
請求項1~3のいずれか1項に記載の核酸配列;
c9orf72センス転写産物特異的阻害剤;および
c9orf72アンチセンス転写産物特異的阻害剤
を含む、導入遺伝子発現カセット。 promoter;
Nucleic acid sequence according to any one of claims 1 to 3;
c9orf72 sense transcript-specific inhibitor; and
Transgene expression cassette containing c9orf72 antisense transcript-specific inhibitor.
プロモーター;
および請求項1~3のいずれか1項に記載の少なくとも1種の核酸
を挿入するステップを含む、組み換えアデノ随伴ウイルス(rAAV)ベクターの作製方法。 to adeno-associated virus (AAV) vectors.
promoter;
and a method for producing a recombinant adeno-associated virus (rAAV) vector, comprising the step of inserting at least one nucleic acid according to any one of claims 1 to 3.
プロモーター;
請求項1~3のいずれか1項に記載の少なくとも1種の核酸;
c9orf72センス転写産物特異的阻害剤;および
c9orf72アンチセンス転写産物特異的阻害剤
を挿入するステップを含む、組み換えアデノ随伴ウイルス(rAAV)ベクターの作製方法。 to adeno-associated virus (AAV) vectors.
promoter;
at least one nucleic acid according to any one of claims 1 to 3;
c9orf72 sense transcript-specific inhibitor; and
A method for producing a recombinant adeno-associated virus (rAAV) vector comprising inserting a c9orf72 antisense transcript-specific inhibitor.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201962924351P | 2019-10-22 | 2019-10-22 | |
US62/924,351 | 2019-10-22 | ||
PCT/US2020/056905 WO2021081236A1 (en) | 2019-10-22 | 2020-10-22 | Triple function adeno-associated virus (aav) vectors for the treatment of c9orf72 associated diseases |
Publications (2)
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JP2023501897A JP2023501897A (en) | 2023-01-20 |
JPWO2021081236A5 true JPWO2021081236A5 (en) | 2023-10-30 |
Family
ID=75620858
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JP2022523436A Pending JP2023501897A (en) | 2019-10-22 | 2020-10-22 | Triple functional adeno-associated virus (AAV) vectors for the treatment of C9ORF72-associated diseases |
Country Status (10)
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US (2) | US20210147873A1 (en) |
EP (1) | EP4048794A4 (en) |
JP (1) | JP2023501897A (en) |
KR (1) | KR20230019063A (en) |
CN (1) | CN116134134A (en) |
AU (1) | AU2020370291A1 (en) |
CA (1) | CA3158518A1 (en) |
IL (1) | IL292384A (en) |
MX (1) | MX2022004771A (en) |
WO (1) | WO2021081236A1 (en) |
Families Citing this family (3)
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EP4347822A2 (en) * | 2021-06-04 | 2024-04-10 | Alnylam Pharmaceuticals, Inc. | Human chromosome 9 open reading frame 72 (c9orf72) irna agent compositions and methods of use thereof |
WO2023077153A1 (en) * | 2021-11-01 | 2023-05-04 | University Of Florida Research Foundation, Incorporated | Poly-ga proteins in alzheimer's disease |
WO2023133574A1 (en) * | 2022-01-10 | 2023-07-13 | The Trustees Of The University Of Pennsylvania | Compositions and methods useful for treatment of c9orf72-mediated disorders |
Family Cites Families (5)
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JP5704361B2 (en) * | 2010-10-27 | 2015-04-22 | 学校法人自治医科大学 | Adeno-associated virus virion for gene transfer into nervous system cells |
US9096671B2 (en) * | 2011-06-29 | 2015-08-04 | Consejo Superior De Investigaciones Cientificas (Csic) | LRP1 as key receptor for the transfer of sterified cholesterol from very-low-density lipoproteins (VLDL) to ischaemic cardiac muscle |
US9896729B2 (en) * | 2011-08-31 | 2018-02-20 | The University Of Manchester | Method for diagnosing a neurodegenerative disease |
EP3452101A2 (en) * | 2016-05-04 | 2019-03-13 | CureVac AG | Rna encoding a therapeutic protein |
US20210261981A1 (en) * | 2017-10-23 | 2021-08-26 | Prevail Therapeutics, Inc. | Gene therapies for neurodegenerative diseases |
-
2020
- 2020-10-22 MX MX2022004771A patent/MX2022004771A/en unknown
- 2020-10-22 CA CA3158518A patent/CA3158518A1/en active Pending
- 2020-10-22 KR KR1020227017065A patent/KR20230019063A/en active Search and Examination
- 2020-10-22 AU AU2020370291A patent/AU2020370291A1/en active Pending
- 2020-10-22 EP EP20878214.4A patent/EP4048794A4/en active Pending
- 2020-10-22 IL IL292384A patent/IL292384A/en unknown
- 2020-10-22 WO PCT/US2020/056905 patent/WO2021081236A1/en unknown
- 2020-10-22 CN CN202080089426.2A patent/CN116134134A/en active Pending
- 2020-10-22 US US17/077,682 patent/US20210147873A1/en not_active Abandoned
- 2020-10-22 JP JP2022523436A patent/JP2023501897A/en active Pending
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2023
- 2023-04-24 US US18/138,361 patent/US20240067984A1/en active Pending
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