JPWO2021058830A5 - - Google Patents
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- JPWO2021058830A5 JPWO2021058830A5 JP2022519283A JP2022519283A JPWO2021058830A5 JP WO2021058830 A5 JPWO2021058830 A5 JP WO2021058830A5 JP 2022519283 A JP2022519283 A JP 2022519283A JP 2022519283 A JP2022519283 A JP 2022519283A JP WO2021058830 A5 JPWO2021058830 A5 JP WO2021058830A5
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Description
本出願は、2019年9月27日出願の英国特許出願番号第1913974.0号の優先権を主張し、その内容は引用により本明細書中に組み込まれている。上記明細書で挙げられた全ての文献は、引用により本明細書に組込まれている。記載された本発明の実施態様の、本発明の範囲及び精神から逸脱することのない、様々な改変及び変形は、当業者に明らかであろう。本発明は、特定の好ましい実施態様に関して記載されているが、特許請求された本発明は、これら特定の実施態様に過度に限定されるべきでないことを理解されたい。実際、本発明を実施するために記載された様式の当業者に明らかな様々な改変は、下記特許請求の範囲内にあることが意図されている。
本件出願は、以下の態様の発明を提供する。
（態様１）
目的のポリペプチドをコードするポリヌクレオチド配列に作動可能に連結されている、(i)ヒト成長ホルモンイントロン3(hGHi3)配列、(ii)シナプシンプロモーター配列、及び／又は(iii)プログラニュリン3'非翻訳領域(UTR)配列、を含む核酸を含む、アデノ随伴ウイルス(AAV)ベクター。
（態様２）
プログラニュリンをコードするポリヌクレオチド配列を含み、該ポリヌクレオチド配列は配列番号4と少なくとも95 %の配列同一性を有する、アデノ随伴ウイルス(AAV)ベクター。
（態様３）
hGHi3配列を含む、態様1又は2に記載のAAVベクター。
（態様４）
前記hGHi3配列は、配列番号7の配列又はそのバリアント若しくはホモログを含む、態様3に記載のAAVベクター。
（態様５）
前記目的のポリペプチドは、プログラニュリン(PGRN)であり、好ましくは配列番号16の配列又はそのバリアント若しくはホモログを含む、態様1～4のいずれか1項に記載のAAVベクター。
（態様６）
前記ポリヌクレオチド配列はコドン最適化されている、態様1～5のいずれか1項に記載のAAVベクター。
（態様７）
前記ポリヌクレオチド配列は、ヒト内での発現のためにコドン最適化されている、態様6に記載のAAVベクター。
（態様８）
前記核酸は更にエクソン性スプライシングエレメント(ESE)を含む、態様1～7のいずれか1項に記載のAAVベクター。
（態様９）
前記ESEは前記ポリヌクレオチドコード配列の上流にある、態様8に記載のAAVベクター。
（態様１０）
前記ESEは、5'隣接配列の一部であるか又は5'隣接配列内に挿入される、態様9に記載のAAVベクター。
（態様１１）
前記ESEは、ガイド配列の一部であるか、又はガイド配列内に挿入されるか、又はガイド配列の一部である、態様8～10のいずれか1項に記載のAAVベクター。
（態様１２）
前記ESEは、野生型ポリヌクレオチド配列由来の5'隣接配列の一部である、態様6に従属する場合の態様8～11のいずれか1項に記載のAAVベクター。
（態様１３）
前記5'隣接配列は野生型GRN由来の5'ガイド配列である、態様10～12のいずれか1項に記載のAAVベクター。
（態様１４）
前記野生型GRNの5'ガイド配列は350～450塩基対を含む、態様13に記載のAAVベクター。
（態様１５）
プログラニュリン3'非翻訳領域(UTR)配列を含み、好ましくは該3'UTR配列は、配列番号14の配列、又はそのホモログのバリアントを含む、態様1～14のいずれか1項に記載のAAVベクター。
（態様１６）
前記ポリヌクレオチド配列はhGH由来のシグナル配列を含む、態様1～15のいずれか1項に記載のAAVベクター。
（態様１７）
前記hGHシグナル配列は配列番号9の配列又はそのバリアント若しくはホモログを含む、態様16に記載のAAVベクター。
（態様１８）
前記hGHシグナル配列はGRNの塩基対1～51と置き換わる、態様16又は17に記載のAAVベクター。
（態様１９）
前記コドン最適化された配列は、配列番号2、配列番号3又は配列番号4の配列、又はそれらのバリアント若しくはホモログ、好ましくは配列番号4を含む、態様6～18のいずれか1項に記載のAAVベクター。
（態様２０）
前記核酸はニューロン特異的プロモーターを含む、態様1～19のいずれか1項に記載のAAVベクター。
（態様２１）
前記ニューロン特異的プロモーターはシナプシンプロモーターを含む、態様20に記載のAAVベクター。
（態様２２）
前記シナプシンプロモーターは配列番号15の配列又はそのバリアント若しくはホモログを含む、態様21に記載のAAVベクター。
（態様２３）
前記AAVベクターは血清型AAV9のAAVベクターである、態様1～22のいずれか1項に記載のAAVベクター。
（態様２４）
前記AAVベクターは、配列番号17と少なくとも85 %の配列同一性を有するポリヌクレオチド配列を含む、態様1～23のいずれか1項に記載のAAVベクター。
（態様２５）
プログラニュリン(PGRN)をコードするポリヌクレオチド配列に作動可能に連結されている、(i)ヒト成長ホルモンイントロン3(hGHi3)配列、(ii)シナプシンプロモーター配列及び／又は(iii)プログラニュリン3'非翻訳領域(UTR)配列、を含む核酸。
（態様２６）
配列番号4と少なくとも81.34 %の配列同一性を有するポリヌクレオチド配列、を含む核酸。
（態様２７）
ニューロン特異的プロモーターを含む、態様25又は26に記載の核酸。
（態様２８）
更に1以上のAAV逆位末端反復を含む、態様25～27のいずれか1項に記載の核酸。
（態様２９）
AAVベクター内での使用に好適であり、態様25～28のいずれか1項に記載の核酸を含む発現カセット。
（態様３０）
態様1～24のいずれか1項に記載のAAVベクター、並びに1以上の医薬的若しくは生理学的に許容し得る、キャリア、賦形剤及び／又は希釈剤を含む、医薬組成物又は医薬品。
（態様３１）
神経障害の治療に使用するための、態様30に記載の医薬組成物又は医薬品。
（態様３２）
前記神経障害には、前頭側頭型認知症(FTD)、神経セロイドリポフスチン症(NCL11)、筋萎縮性側索硬化症(ALS)、ハンチントン病、パーキンソン病、アルツハイマー病及び他の神経障害が含まれる、態様31に記載の使用のための医薬組成物又は医薬品。
（態様３３）
(i)ヘテロ接合型、ホモ接合型若しくは複合ヘテロ接合型のGRN変異である対象、(ii)孤発性神経疾患に罹患している対象、及び／又は(iii)生理学的に正常なレベルより低いPGRNレベルを有する対象、の治療に使用するための、態様31又は32に記載の使用のための医薬組成物又は医薬品。
This application claims priority from UK Patent Application No. 1913974.0, filed 27 September 2019, the contents of which are incorporated herein by reference. All documents cited in the above specification are herein incorporated by reference. Various modifications and variations of the described embodiments of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described with respect to certain preferred embodiments, it should be understood that the invention as claimed is not unduly limited to these specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the following claims.
The present application provides the following aspects of the invention.
(Aspect 1)
(i) a human growth hormone intron 3 (hGHi3) sequence, (ii) a synapsin promoter sequence, and/or (iii) progranulin 3 operably linked to a polynucleotide sequence encoding a polypeptide of interest. 'An adeno-associated virus (AAV) vector comprising a nucleic acid comprising an untranslated region (UTR) sequence.
(Aspect 2)
An adeno-associated virus (AAV) vector comprising a polynucleotide sequence encoding progranulin, the polynucleotide sequence having at least 95% sequence identity with SEQ ID NO:4.
(Aspect 3)
The AAV vector according to embodiment 1 or 2, comprising the hGHi3 sequence.
(Aspect 4)
The AAV vector according to aspect 3, wherein the hGHi3 sequence comprises the sequence SEQ ID NO: 7 or a variant or homologue thereof.
(Aspect 5)
The AAV vector according to any one of aspects 1 to 4, wherein the polypeptide of interest is progranulin (PGRN), preferably comprising the sequence SEQ ID NO: 16 or a variant or homologue thereof.
(Aspect 6)
AAV vector according to any one of embodiments 1 to 5, wherein said polynucleotide sequence is codon optimized.
(Aspect 7)
7. AAV vector according to embodiment 6, wherein said polynucleotide sequence is codon optimized for expression in humans.
(Aspect 8)
The AAV vector according to any one of embodiments 1 to 7, wherein the nucleic acid further comprises an exonic splicing element (ESE).
(Aspect 9)
9. AAV vector according to embodiment 8, wherein said ESE is upstream of said polynucleotide coding sequence.
(Aspect 10)
10. AAV vector according to embodiment 9, wherein the ESE is part of or inserted within the 5' flanking sequence.
(Aspect 11)
The AAV vector according to any one of aspects 8 to 10, wherein the ESE is part of, inserted within, or part of the guide sequence.
(Aspect 12)
AAV vector according to any one of embodiments 8 to 11 when dependent on embodiment 6, wherein said ESE is part of the 5' flanking sequence derived from the wild-type polynucleotide sequence.
(Aspect 13)
The AAV vector according to any one of aspects 10 to 12, wherein the 5' flanking sequence is a 5' guide sequence derived from wild-type GRN.
(Aspect 14)
14. The AAV vector according to embodiment 13, wherein the 5' guide sequence of the wild-type GRN comprises 350 to 450 base pairs.
(Aspect 15)
15, comprising a progranulin 3' untranslated region (UTR) sequence, preferably said 3' UTR sequence comprising the sequence SEQ ID NO: 14, or a variant of a homolog thereof. AAV vector.
(Aspect 16)
16. AAV vector according to any one of embodiments 1 to 15, wherein the polynucleotide sequence comprises a signal sequence derived from hGH.
(Aspect 17)
17. The AAV vector according to embodiment 16, wherein the hGH signal sequence comprises the sequence SEQ ID NO: 9 or a variant or homologue thereof.
(Aspect 18)
18. The AAV vector according to embodiment 16 or 17, wherein the hGH signal sequence replaces base pairs 1 to 51 of GRN.
(Aspect 19)
19. The codon-optimized sequence according to any one of aspects 6 to 18, wherein the codon-optimized sequence comprises the sequence SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 4, or a variant or homolog thereof, preferably SEQ ID NO: 4. AAV vector.
(Aspect 20)
The AAV vector according to any one of embodiments 1 to 19, wherein the nucleic acid comprises a neuron-specific promoter.
(Aspect 21)
21. The AAV vector according to embodiment 20, wherein the neuron-specific promoter comprises a synapsin promoter.
(Aspect 22)
22. The AAV vector according to embodiment 21, wherein the synapsin promoter comprises the sequence SEQ ID NO: 15 or a variant or homologue thereof.
(Aspect 23)
The AAV vector according to any one of aspects 1 to 22, wherein the AAV vector is an AAV vector of serotype AAV9.
(Aspect 24)
24. AAV vector according to any one of aspects 1 to 23, wherein said AAV vector comprises a polynucleotide sequence having at least 85% sequence identity with SEQ ID NO: 17.
(Aspect 25)
operably linked to a polynucleotide sequence encoding progranulin (PGRN); (i) a human growth hormone intron 3 (hGHi3) sequence; (ii) a synapsin promoter sequence; and/or (iii) progranulin. A nucleic acid comprising a 3' untranslated region (UTR) sequence.
(Aspect 26)
A nucleic acid comprising a polynucleotide sequence having at least 81.34% sequence identity with SEQ ID NO:4.
(Aspect 27)
27. The nucleic acid according to embodiment 25 or 26, comprising a neuron-specific promoter.
(Aspect 28)
28. A nucleic acid according to any one of embodiments 25 to 27, further comprising one or more AAV inverted terminal repeats.
(Aspect 29)
An expression cassette suitable for use in an AAV vector and comprising a nucleic acid according to any one of aspects 25 to 28.
(Aspect 30)
A pharmaceutical composition or medicament comprising an AAV vector according to any one of aspects 1 to 24 and one or more pharmaceutically or physiologically acceptable carriers, excipients and/or diluents.
(Aspect 31)
A pharmaceutical composition or medicament according to embodiment 30 for use in the treatment of neurological disorders.
(Aspect 32)
The neurological disorders include frontotemporal dementia (FTD), neuronal ceroid lipofuscinosis (NCL11), amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, Alzheimer's disease and other neurological disorders. A pharmaceutical composition or medicament for use according to embodiment 31, comprising:
(Aspect 33)
(i) subjects who are heterozygous, homozygous, or compound heterozygous for a GRN mutation; (ii) subjects suffering from a sporadic neurological disease; and/or (iii) below physiologically normal levels. A pharmaceutical composition or medicament for use according to aspect 31 or 32 for use in the treatment of a subject having low PGRN levels.
Claims (30)
(ii)シナプシンプロモーター配列;
(iii)プログラニュリン(PGRN)をコードするポリヌクレオチドコード配列;及び
(iv)PGRNの3'非翻訳領域(UTR)配列、
を含む核酸を含む、アデノ随伴ウイルス(AAV)ベクター。 (i) Human growth hormone intron 3 (hGHi3) sequence;
(ii) synapsin promoter sequence;
(iii) a polynucleotide coding sequence encoding progranulin (PGRN); and
(iv) PGRN 3' untranslated region (UTR) sequence,
An adeno-associated virus (AAV) vector comprising a nucleic acid comprising.
(ii)シナプシンプロモーター配列;
(iii)PGRNをコードするポリヌクレオチド配列;及び
(iv)PGRNの3'UTR配列、
を含む核酸。 (i) hGHi3 sequence;
(ii) synapsin promoter sequence;
(iii) a polynucleotide sequence encoding PGRN; and
(iv) PGRN 3'UTR sequence,
Nucleic acid containing.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB201913974A GB201913974D0 (en) | 2019-09-27 | 2019-09-27 | Vector |
| GB1913974.0 | 2019-09-27 | ||
| PCT/EP2020/077144 WO2021058830A1 (en) | 2019-09-27 | 2020-09-28 | Vector |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2022549892A JP2022549892A (en) | 2022-11-29 |
| JPWO2021058830A5 true JPWO2021058830A5 (en) | 2023-10-12 |
Family
ID=68538788
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022519283A Pending JP2022549892A (en) | 2019-09-27 | 2020-09-28 | vector |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US20220380804A1 (en) |
| EP (1) | EP4034664A1 (en) |
| JP (1) | JP2022549892A (en) |
| CN (1) | CN114450413B (en) |
| AU (1) | AU2020354538A1 (en) |
| CA (1) | CA3155742A1 (en) |
| GB (1) | GB201913974D0 (en) |
| WO (1) | WO2021058830A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA3228916A1 (en) * | 2021-08-11 | 2023-02-16 | King's College London | Compositions and methods for improved treatment of disorders affecting the central nervous system |
| CN116064624A (en) * | 2022-09-15 | 2023-05-05 | 思鹏生物科技(苏州)有限公司 | Method for promoting stable expression of vector by utilizing RPL gene and functional gene thereof |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0173552B1 (en) | 1984-08-24 | 1991-10-09 | The Upjohn Company | Recombinant dna compounds and the expression of polypeptides such as tpa |
| EP0932694A2 (en) | 1996-09-11 | 1999-08-04 | THE UNITED STATES GOVERNMENT as represented by THE DEPARTMENT OF HEALTH AND HUMAN SERVICES | Aav4 vector and uses thereof |
| US6156303A (en) | 1997-06-11 | 2000-12-05 | University Of Washington | Adeno-associated virus (AAV) isolates and AAV vectors derived therefrom |
| DE69939169D1 (en) | 1998-05-28 | 2008-09-04 | Us Gov Health & Human Serv | AAV5 VECTORS AND THEIR USE |
| ES2288037T3 (en) | 1998-11-05 | 2007-12-16 | The Trustees Of The University Of Pennsylvania | SEQUENCE OF NUCLEIC ACID OF THE ASSOCIATED ADENOVIRUS SEROTIPE 1, VECTORS AND CELLS THAT CONTAIN THEM. |
| AU2003223766A1 (en) * | 2002-04-30 | 2003-11-17 | University Of North Carolina At Chapel Hill | Secretion signal vectors |
| WO2008019187A2 (en) * | 2006-05-30 | 2008-02-14 | Mayo Foundation For Medical Education And Research | Detecting and treating dementia |
| HRP20220036T1 (en) | 2011-04-22 | 2022-04-01 | The Regents Of The University Of California | Adeno-associated virus virions with variant capsid and methods of use thereof |
| EP3327127B1 (en) * | 2012-12-12 | 2021-03-24 | The Broad Institute, Inc. | Delivery, engineering and optimization of systems, methods and compositions for sequence manipulation and therapeutic applications |
| JP6738728B2 (en) * | 2013-06-17 | 2020-08-19 | ザ・ブロード・インスティテュート・インコーポレイテッド | Delivery and use of CRISPR-Cas systems, vectors and compositions for liver targeting and therapy |
| EP3632923A1 (en) * | 2015-01-16 | 2020-04-08 | Voyager Therapeutics, Inc. | Central nervous system targeting polynucleotides |
| DK3387137T3 (en) * | 2015-12-11 | 2021-05-03 | California Inst Of Techn | TARGET TIPPID TIMES FOR MANAGING ADENO-ASSOCIATED VIRUSES (AAVs) |
| EP3423109A4 (en) | 2016-03-02 | 2019-08-14 | The Children's Hospital of Philadelphia | Therapy for frontotemporal dementia |
| MX2020003965A (en) * | 2017-10-03 | 2020-10-05 | Prevail Therapeutics Inc | Gene therapies for lysosomal disorders. |
| CA3083765A1 (en) * | 2017-12-01 | 2019-06-06 | Encoded Therapeutics, Inc. | Engineered dna binding proteins |
| KR102171360B1 (en) * | 2018-06-22 | 2020-10-28 | 재단법인대구경북과학기술원 | Cytokine fusion polypeptide and cytokine library comprising the same |
| MX2021008542A (en) * | 2019-01-18 | 2021-11-12 | Voyager Therapeutics Inc | Methods and systems for producing aav particles. |
| BR112021015817A2 (en) * | 2019-02-22 | 2021-10-13 | The Trustees Of The University Of Pennsylvania | RECOMBINANT ADENO-ASSOCIATED VIRUS FOR ADULT-ONSET NEURODEGENERATION TREATMENT ASSOCIATED WITH GRN |
-
2019
- 2019-09-27 GB GB201913974A patent/GB201913974D0/en not_active Ceased
-
2020
- 2020-09-28 AU AU2020354538A patent/AU2020354538A1/en active Pending
- 2020-09-28 WO PCT/EP2020/077144 patent/WO2021058830A1/en active Application Filing
- 2020-09-28 CA CA3155742A patent/CA3155742A1/en active Pending
- 2020-09-28 JP JP2022519283A patent/JP2022549892A/en active Pending
- 2020-09-28 EP EP20781509.3A patent/EP4034664A1/en active Pending
- 2020-09-28 CN CN202080067598.XA patent/CN114450413B/en active Active
- 2020-09-28 US US17/763,644 patent/US20220380804A1/en active Pending
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