JPWO2021195214A5 - - Google Patents
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- JPWO2021195214A5 JPWO2021195214A5 JP2022557749A JP2022557749A JPWO2021195214A5 JP WO2021195214 A5 JPWO2021195214 A5 JP WO2021195214A5 JP 2022557749 A JP2022557749 A JP 2022557749A JP 2022557749 A JP2022557749 A JP 2022557749A JP WO2021195214 A5 JPWO2021195214 A5 JP WO2021195214A5
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- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 28
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Description
参考文献
特許及び特許出願を含むがこれらに限定されない、本明細書及び本明細書の実施例で引用される全ての刊行物及び参考文献は、あたかも個々の刊行物又は参考文献が、完全に記載されるように参照により本明細書に組み込まれることが具体的かつ個別に示されるかのように、それらの全体が参照により組み込まれる。この出願が優先権を主張する任意の特許出願もまた、刊行物及び参考文献について上述した方法で、参照により本明細書に組み込まれる。
本発明は、例えば、以下を提供する。
(項目1)
カプシド不含閉端DNA(ceDNA)ベクターであって、
隣接する逆方向末端反復配列(ITR)間に少なくとも1つの核酸配列を含み、前記少なくとも1つの核酸配列が、少なくとも1つのFIXタンパク質をコードする、ceDNAベクター。
(項目2)
前記少なくとも1つのFIXタンパク質をコードする少なくとも1つの核酸配列が、表1に示される配列のうちのいずれか、又は表12に列挙される任意のceDNA配列に含まれる任意のオープンリーディングフレーム(ORF)配列から選択される、項目1に記載のceDNAベクター。
(項目3)
前記ceDNAベクターが、前記少なくとも1つのFIXタンパク質をコードする少なくとも1つの核酸配列に作動可能に連結された、表7のプロモーター配列のうちのいずれかから選択されるプロモーター配列を含む、項目1又は2に記載のceDNAベクター。
(項目4)
前記ceDNAベクターが、表8のエンハンサー配列のうちのいずれかから選択されるエンハンサー配列を含む、項目1~3のいずれか一項に記載のceDNAベクター。
(項目5)
前記ceDNAベクターが、表9Aの5’UTR及び/又はイントロン配列のうちのいずれかから選択される5’UTR及び/又はイントロン配列を含む、項目1~4のいずれか一項に記載のceDNAベクター。
(項目6)
前記ceDNAベクターが、表9Bの3’UTR配列のうちのいずれかから選択される3’UTR配列を含む、項目1~5のいずれか一項に記載のceDNAベクター。
(項目7)
前記ceDNAベクターが、表10のポリA配列のうちのいずれかから選択される少なくとも1つのポリA配列を含む、項目1~6のいずれか一項に記載のceDNAベクター。
(項目8)
前記ceDNAベクターが、少なくとも1つの核酸配列に作動可能に連結された少なくとも1つのプロモーター配列を含む、項目1~7のいずれか一項に記載のceDNAベクター。
(項目9)
前記少なくとも1つの核酸配列が、cDNAである、項目1~8のいずれか一項に記載のceDNAベクター。
(項目10)
少なくとも1つのITRが、機能的末端分解部位及びRep結合部位を含む、項目1~9のいずれか一項に記載のceDNAベクター。
(項目11)
前記ITRの一方又は両方が、パルボウイルス、ディペンドウイルス、及びアデノ随伴ウイルス(AAV)から選択されるウイルスに由来する、項目1~10のいずれか一項に記載のceDNAベクター。
(項目12)
前記隣接するITRが、互いに対して対称又は非対称である、項目1~11のいずれか一項に記載のceDNAベクター。
(項目13)
前記隣接するITRが、対称又は実質的に対称である、項目12に記載のceDNAベクター。
(項目14)
前記隣接するITRが、非対称である、項目12に記載のceDNAベクター。
(項目15)
前記ITRの一方若しくは両方が野生型であるか、又は前記ITRの両方が野生型ITRである、項目1~14のいずれか一項に記載のceDNAベクター。
(項目16)
前記隣接するITRが、異なるウイルス血清型に由来する、項目1~15のいずれか一項に記載のceDNAベクター。
(項目17)
前記隣接するITRが、表2に示されるウイルス血清型のいずれかの対から選択される、項目1~16のいずれか一項に記載のceDNAベクター。
(項目18)
前記ITRの一方又は両方が、表3の配列のうちの1つ以上から選択される配列を含む、項目1~17のいずれか一項に記載のceDNAベクター。
(項目19)
前記ITRの少なくとも一方が、野生型AAV ITR配列から、前記ITRの全体的な三次元立体構造に影響を与える欠失、付加、又は置換によって変更されている、項目1~18のいずれか一項に記載のceDNAベクター。
(項目20)
前記ITRの一方又は両方が、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、及びAAV12から選択されるAAV血清型に由来する、項目1~19のいずれか一項に記載のceDNAベクター。
(項目21)
前記ITRの一方又は両方が、合成である、項目1~20のいずれか一項に記載のceDNAベクター。
(項目22)
前記ITRの一方若しくは両方が野生型ITRでないか、又は前記ITRの両方が野生型ITRでない、項目1~21のいずれか一項に記載のceDNAベクター。
(項目23)
前記ITRの一方又は両方が、A、A’、B、B’、C、C’、D、及びD’から選択されるITR領域のうちの少なくとも1つにおける欠失、挿入、及び/又は置換によって修飾されている、項目1~22のいずれか一項に記載のceDNAベクター。
(項目24)
前記欠失、挿入、及び/又は置換が、通常は前記A、A’、B、B’、C、又はC’領域によって形成されるステムループ構造の全部又は一部の欠失をもたらす、項目23に記載のceDNAベクター。
(項目25)
前記ITRの一方又は両方が、通常は前記B及びB’領域によって形成されるステムループ構造の全部又は一部の欠失をもたらす、欠失、挿入、及び/又は置換によって修飾されている、項目1~24のいずれか一項に記載のceDNAベクター。
(項目26)
前記ITRの一方又は両方が、通常は前記C及びC’領域によって形成されるステムループ構造の全部又は一部の欠失をもたらす、欠失、挿入、及び/又は置換によって修飾されている、項目1~24のいずれか一項に記載のceDNAベクター。
(項目27)
前記ITRの一方又は両方が、通常は前記B及びB’領域によって形成されるステムループ構造の一部、並びに/又は通常は前記C及びC’領域によって形成されるステムループ構造の一部の欠失をもたらす、欠失、挿入、及び/又は置換によって修飾されている、項目1~24のいずれか一項に記載のceDNAベクター。
(項目28)
前記ITRの一方又は両方が、通常は前記B及びB’領域によって形成される第1のステムループ構造と、前記C及びC’領域によって形成される第2のステムループ構造とを含む領域に、単一のステムループ構造を含む、項目1~27のいずれか一項に記載のceDNAベクター。
(項目29)
前記ITRの一方又は両方が、通常は前記B及びB’領域によって形成される第1のステムループ構造と、前記C及びC’領域によって形成される第2のステムループ構造とを含む領域に、単一のステム及び2つのループを含む、項目1~28のいずれか一項に記載のceDNAベクター。
(項目30)
前記ITRの一方又は両方が、通常は前記B及びB’領域によって形成される第1のステムループ構造と、前記C及びC’領域によって形成される第2のステムループ構造とを含む領域に、単一のステム及び単一のループを含む、項目1~29のいずれか一項に記載のceDNAベクター。
(項目31)
両方のITRが、前記ITRが互いに対して反転されたときに全体的な三次元対称性をもたらすような様式で変更されている、項目1~30のいずれか一項に記載のceDNAベクター。
(項目32)
前記ITRの一方又は両方が、表3、5A、5B、及び6に示される配列から選択される核酸配列を含む、項目1~31のいずれか一項に記載のceDNAベクター。
(項目33)
少なくとも1つの核酸配列が、少なくとも1つの調節スイッチの制御下にある、項目1~32のいずれか一項に記載のceDNAベクター。
(項目34)
前記少なくとも1つの調節スイッチが、バイナリ調節スイッチ、小分子調節スイッチ、パスコード調節スイッチ、核酸ベース調節スイッチ、転写後調節スイッチ、放射線制御又は超音波制御の調節スイッチ、低酸素媒介調節スイッチ、炎症反応調節スイッチ、剪断活性化調節スイッチ、及びキルスイッチからなる群から選択される、項目33に記載のceDNAベクター。
(項目35)
表12から選択される核酸配列を含む、カプシド不含閉端DNA(ceDNA)ベクター。
(項目36)
配列番号404、配列番号405又は配列番号406と少なくとも85%同一である核酸配列を含む、カプシド不含閉端DNA(ceDNA)ベクター。
(項目37)
配列番号404、配列番号405及び配列番号406からなる群から選択される核酸配列からなる、カプシド不含閉端DNA(ceDNA)ベクター。
(項目38)
細胞におけるFIXタンパク質を発現する方法であって、前記細胞を項目1~37のいずれか一項に記載のceDNAベクターと接触させることを含む、方法。
(項目39)
前記細胞が、肝細胞である、項目38に記載の方法。
(項目40)
前記細胞が、インビトロ又はインビボにある、項目38又は39に記載の方法。
(項目41)
前記少なくとも1つの核酸配列が、真核細胞における発現のためにコドン最適化される、項目38~40のいずれか一項に記載の方法。
(項目42)
前記コドン最適化された少なくとも1つの核酸配列が、表1に示される配列のうちのいずれか1つ、又は表12に列挙される任意のceDNA配列に含まれる任意のオープンリーディングフレーム(ORF)配列から選択される、項目38~41のいずれか一項に記載の方法。
(項目43)
血友病Bを有する対象を治療する方法であって、項目1~37のいずれか一項に記載のceDNAベクターを前記対象に投与することを含み、少なくとも1つの核酸配列が、少なくとも1つのFIXタンパク質をコードする、方法。
(項目44)
前記少なくとも1つのFIXタンパク質をコードする前記少なくとも1つの核酸配列が、表1に示される配列のうちのいずれか1つから選択される、項目43に記載の方法。
(項目45)
前記ceDNAベクターが、肝細胞に投与される、項目43又は44に記載の方法。
(項目46)
前記ceDNAベクターが、肝細胞において前記FIXタンパク質を発現する、項目44又は45に記載の方法。
(項目47)
前記ceDNAベクターが、静脈内又は筋肉内注射により投与される、項目44~46のいずれか一項に記載の方法。
(項目48)
前記対象に免疫調節剤を投与することを更に含む、項目44~47のいずれか一項に記載の方法。
(項目49)
前記免疫調節剤が、免疫抑制剤である、項目48に記載の方法。
(項目50)
前記免疫抑制剤が、チロシンキナーゼ阻害剤(TKI)である、項目49に記載の方法。
(項目51)
前記TKIが、約0.5mg/kg~約700mg/kgの用量で前記対象に投与される、項目50に記載の方法。
(項目52)
項目1~37のいずれか一項に記載のceDNAベクターを含む、医薬組成物。
(項目53)
追加の化合物を更に含む、項目52に記載の医薬組成物。
(項目54)
前記追加の化合物が、免疫調節剤である、項目52に記載の医薬組成物。
(項目55)
前記免疫調節剤が、免疫抑制剤である、項目54に記載の医薬組成物。
(項目56)
前記免疫抑制剤が、チロシンキナーゼ阻害剤(TKI)である、項目55に記載の医薬組成物。
(項目57)
前記組成物が、賦形剤又は担体を更に含む、項目56に記載の医薬組成物。
(項目58)
項目1~37のいずれか一項に記載のceDNAベクターを含有する、細胞。
(項目59)
前記細胞が、肝細胞である、項目58に記載の細胞。
(項目60)
項目1~37のいずれか一項に記載のceDNAベクター及び脂質を含む、組成物。
(項目61)
前記脂質が、脂質ナノ粒子(LNP)である、項目60に記載の組成物。
(項目62)
項目1~37のいずれか一項に記載のceDNAベクター、項目52~57のいずれか一項に記載の組成物、又は項目58に記載の細胞を含むキット。
All publications and references cited in this specification and the examples herein, including but not limited to patents and patent applications, are incorporated by reference in their entirety as if each individual publication or reference was specifically and individually indicated to be incorporated by reference herein as if fully set forth. Any patent application to which this application claims priority is also incorporated by reference herein in the manner described above for publications and references.
The present invention provides, for example, the following:
(Item 1)
A capsid-free closed-ended DNA (ceDNA) vector, comprising:
A ceDNA vector comprising at least one nucleic acid sequence between adjacent inverted terminal repeats (ITRs), said at least one nucleic acid sequence encoding at least one FIX protein.
(Item 2)
2. The ceDNA vector of claim 1, wherein the at least one nucleic acid sequence encoding the at least one FIX protein is selected from any of the sequences shown in Table 1, or any open reading frame (ORF) sequence contained in any of the ceDNA sequences listed in Table 12.
(Item 3)
3. The ceDNA vector of claim 1 or 2, wherein the ceDNA vector comprises a promoter sequence selected from any of the promoter sequences in Table 7, operably linked to at least one nucleic acid sequence encoding the at least one FIX protein.
(Item 4)
4. The ceDNA vector of any one of items 1 to 3, wherein the ceDNA vector comprises an enhancer sequence selected from any of the enhancer sequences in Table 8.
(Item 5)
5. The ceDNA vector of any one of items 1 to 4, wherein the ceDNA vector comprises a 5'UTR and/or intron sequence selected from any of the 5'UTR and/or intron sequences of Table 9A.
(Item 6)
6. The ceDNA vector of any one of items 1 to 5, wherein the ceDNA vector comprises a 3'UTR sequence selected from any of the 3'UTR sequences in Table 9B.
(Item 7)
7. The ceDNA vector of any one of items 1 to 6, wherein the ceDNA vector comprises at least one polyA sequence selected from any of the polyA sequences in Table 10.
(Item 8)
8. The ceDNA vector according to any one of items 1 to 7, wherein the ceDNA vector comprises at least one promoter sequence operably linked to at least one nucleic acid sequence.
(Item 9)
9. The ceDNA vector of any one of items 1 to 8, wherein the at least one nucleic acid sequence is a cDNA.
(Item 10)
10. The ceDNA vector according to any one of items 1 to 9, wherein at least one ITR comprises a functional terminal resolution site and a Rep binding site.
(Item 11)
11. The ceDNA vector of any one of items 1 to 10, wherein one or both of the ITRs are derived from a virus selected from parvovirus, dependovirus, and adeno-associated virus (AAV).
(Item 12)
12. The ceDNA vector of any one of items 1 to 11, wherein the flanking ITRs are symmetric or asymmetric with respect to each other.
(Item 13)
13. The ceDNA vector of item 12, wherein the flanking ITRs are symmetric or substantially symmetric.
(Item 14)
13. The ceDNA vector of claim 12, wherein the flanking ITRs are asymmetric.
(Item 15)
15. The ceDNA vector according to any one of items 1 to 14, wherein one or both of the ITRs are wild-type or both of the ITRs are wild-type ITRs.
(Item 16)
16. The ceDNA vector of any one of items 1 to 15, wherein the flanking ITRs are derived from different viral serotypes.
(Item 17)
17. The ceDNA vector of any one of items 1 to 16, wherein the flanking ITRs are selected from any pair of viral serotypes shown in Table 2.
(Item 18)
18. The ceDNA vector of any one of items 1 to 17, wherein one or both of the ITRs comprise a sequence selected from one or more of the sequences in Table 3.
(Item 19)
19. The ceDNA vector of any one of items 1 to 18, wherein at least one of the ITRs is altered from a wild-type AAV ITR sequence by a deletion, addition, or substitution that affects the overall three-dimensional conformation of the ITR.
(Item 20)
20. The ceDNA vector of any one of items 1 to 19, wherein one or both of the ITRs are derived from an AAV serotype selected from AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAV12.
(Item 21)
21. The ceDNA vector of any one of items 1 to 20, wherein one or both of the ITRs are synthetic.
(Item 22)
22. The ceDNA vector of any one of items 1 to 21, wherein one or both of the ITRs are not wild-type ITRs, or both of the ITRs are not wild-type ITRs.
(Item 23)
23. The ceDNA vector according to any one of the preceding claims, wherein one or both of the ITRs are modified by a deletion, insertion and/or substitution in at least one of the ITR regions selected from A, A', B, B', C, C', D and D'.
(Item 24)
24. The ceDNA vector of item 23, wherein the deletion, insertion and/or substitution results in the deletion of all or part of the stem-loop structure normally formed by the A, A', B, B', C or C' region.
(Item 25)
25. The ceDNA vector according to any one of items 1 to 24, wherein one or both of the ITRs are modified by deletion, insertion and/or substitution, resulting in the deletion of all or part of the stem-loop structure normally formed by the B and B' regions.
(Item 26)
25. The ceDNA vector according to any one of items 1 to 24, wherein one or both of the ITRs are modified by deletion, insertion and/or substitution, resulting in the deletion of all or part of the stem-loop structure normally formed by the C and C' regions.
(Item 27)
25. The ceDNA vector according to any one of items 1 to 24, wherein one or both of the ITRs are modified by a deletion, insertion and/or substitution resulting in the deletion of part of the stem-loop structure normally formed by the B and B' regions and/or of part of the stem-loop structure normally formed by the C and C' regions.
(Item 28)
28. The ceDNA vector according to any one of items 1 to 27, wherein one or both of the ITRs comprise a single stem-loop structure in a region that normally comprises a first stem-loop structure formed by the B and B' regions and a second stem-loop structure formed by the C and C' regions.
(Item 29)
29. The ceDNA vector according to any one of items 1 to 28, wherein one or both of the ITRs comprise a single stem and two loops, usually in a region comprising a first stem-loop structure formed by the B and B' regions and a second stem-loop structure formed by the C and C' regions.
(Item 30)
30. The ceDNA vector according to any one of items 1 to 29, wherein one or both of the ITRs comprise a single stem and a single loop in a region that typically comprises a first stem-loop structure formed by the B and B' regions and a second stem-loop structure formed by the C and C' regions.
(Item 31)
31. The ceDNA vector of any one of items 1 to 30, wherein both ITRs are modified in such a manner as to result in overall three-dimensional symmetry when said ITRs are inverted relative to each other.
(Item 32)
32. The ceDNA vector of any one of items 1 to 31, wherein one or both of the ITRs comprises a nucleic acid sequence selected from the sequences shown in Tables 3, 5A, 5B, and 6.
(Item 33)
33. The ceDNA vector of any one of items 1 to 32, wherein at least one nucleic acid sequence is under the control of at least one regulatory switch.
(Item 34)
34. The ceDNA vector of item 33, wherein the at least one regulatory switch is selected from the group consisting of a binary regulatory switch, a small molecule regulatory switch, a passcode regulatory switch, a nucleic acid-based regulatory switch, a post-transcriptional regulatory switch, a radiation- or ultrasound-controlled regulatory switch, a hypoxia-mediated regulatory switch, an inflammatory response regulatory switch, a shear-activated regulatory switch, and a kill switch.
(Item 35)
A capsid-free closed-ended DNA (ceDNA) vector comprising a nucleic acid sequence selected from Table 12.
(Item 36)
A capsid-free closed-ended DNA (ceDNA) vector comprising a nucleic acid sequence that is at least 85% identical to SEQ ID NO:404, SEQ ID NO:405 or SEQ ID NO:406.
(Item 37)
A capsid-free closed-ended DNA (ceDNA) vector consisting of a nucleic acid sequence selected from the group consisting of SEQ ID NO:404, SEQ ID NO:405 and SEQ ID NO:406.
(Item 38)
38. A method for expressing a FIX protein in a cell, comprising contacting said cell with a ceDNA vector according to any one of items 1 to 37.
(Item 39)
39. The method of claim 38, wherein the cell is a hepatocyte.
(Item 40)
40. The method of claim 38 or 39, wherein the cell is in vitro or in vivo.
(Item 41)
41. The method of any one of items 38 to 40, wherein the at least one nucleic acid sequence is codon-optimized for expression in a eukaryotic cell.
(Item 42)
42. The method of any one of items 38 to 41, wherein the at least one codon-optimized nucleic acid sequence is selected from any one of the sequences shown in Table 1, or any open reading frame (ORF) sequence contained in any ceDNA sequence listed in Table 12.
(Item 43)
38. A method for treating a subject having hemophilia B, comprising administering to the subject a ceDNA vector according to any one of items 1 to 37, wherein at least one nucleic acid sequence encodes at least one FIX protein.
(Item 44)
44. The method of claim 43, wherein the at least one nucleic acid sequence encoding the at least one FIX protein is selected from any one of the sequences shown in Table 1.
(Item 45)
45. The method of claim 43 or 44, wherein the ceDNA vector is administered to a hepatocyte.
(Item 46)
46. The method of claim 44 or 45, wherein the ceDNA vector expresses the FIX protein in hepatocytes.
(Item 47)
47. The method of any one of items 44 to 46, wherein the ceDNA vector is administered by intravenous or intramuscular injection.
(Item 48)
48. The method of any one of claims 44 to 47, further comprising administering to the subject an immunomodulatory agent.
(Item 49)
49. The method of claim 48, wherein the immunomodulatory agent is an immunosuppressant.
(Item 50)
50. The method of claim 49, wherein the immunosuppressant is a tyrosine kinase inhibitor (TKI).
(Item 51)
51. The method of claim 50, wherein the TKI is administered to the subject at a dose of about 0.5 mg/kg to about 700 mg/kg.
(Item 52)
A pharmaceutical composition comprising the ceDNA vector according to any one of items 1 to 37.
(Item 53)
53. The pharmaceutical composition of claim 52, further comprising an additional compound.
(Item 54)
53. The pharmaceutical composition of claim 52, wherein the additional compound is an immunomodulatory agent.
(Item 55)
55. The pharmaceutical composition of claim 54, wherein the immunomodulatory agent is an immunosuppressant.
(Item 56)
56. The pharmaceutical composition of claim 55, wherein the immunosuppressant is a tyrosine kinase inhibitor (TKI).
(Item 57)
57. The pharmaceutical composition of claim 56, wherein the composition further comprises an excipient or carrier.
(Item 58)
A cell containing the ceDNA vector according to any one of items 1 to 37.
(Item 59)
59. The cell of item 58, wherein the cell is a hepatocyte.
(Item 60)
38. A composition comprising the ceDNA vector according to any one of items 1 to 37 and a lipid.
(Item 61)
61. The composition of claim 60, wherein the lipid is a lipid nanoparticle (LNP).
(Item 62)
59. A kit comprising the ceDNA vector of any one of items 1 to 37, the composition of any one of items 52 to 57, or the cell of item 58.
Claims (31)
隣接する逆方向末端反復配列(ITR)間に位置する少なくとも1つの核酸配列を含み、前記少なくとも1つの核酸配列が、少なくとも1つの第IX因子(FIX)タンパク質をコードする、ceDNAベクター。 A capsid-free closed-ended DNA (ceDNA) vector, comprising:
A ceDNA vector comprising at least one nucleic acid sequence located between adjacent inverted terminal repeats (ITRs), said at least one nucleic acid sequence encoding at least one Factor IX ( FIX ) protein.
前記ceDNAベクターが、表8に示される配列のうちのいずれかからなる群から選択されるエンハンサー配列を含む;
前記ceDNAベクターが、表9Aに示される配列のうちのいずれかからなる群から選択される5’UTR及び/又はイントロン配列を含む;
前記ceDNAベクターが、表9Bに示される配列のうちのいずれかからなる群から選択される3’UTR配列を含む;
前記ceDNAベクターが、表10に示される配列のうちのいずれかからなる群から選択される少なくとも1つのポリA配列を含む;及び/又は
前記ceDNAベクターが、前記少なくとも1つの核酸配列に作動可能に連結された少なくとも1つのプロモーター配列を含む、
請求項1又は2に記載のceDNAベクター。 the ceDNA vector comprises a promoter sequence selected from the group consisting of any of the sequences shown in Table 7 linked to the at least one nucleic acid sequence encoding the at least one FIX protein ;
The ceDNA vector comprises an enhancer sequence selected from the group consisting of any of the sequences shown in Table 8;
the ceDNA vector comprises a 5'UTR and/or intron sequence selected from the group consisting of any of the sequences shown in Table 9A;
the ceDNA vector comprises a 3'UTR sequence selected from the group consisting of any of the sequences shown in Table 9B;
The ceDNA vector comprises at least one polyA sequence selected from the group consisting of any of the sequences shown in Table 10; and/or
the ceDNA vector comprises at least one promoter sequence operably linked to the at least one nucleic acid sequence ;
A ceDNA vector according to claim 1 or 2.
前記隣接するITRが、互いに対して対称又は実質的に対称である;又は
前記隣接するITRが、互いに対して非対称である、
請求項1~5のいずれか一項に記載のceDNAベクター。 the adjacent ITRs are symmetric or asymmetric with respect to each other ;
the adjacent ITRs are symmetric or substantially symmetric with respect to each other; or
the adjacent ITRs are asymmetric with respect to each other ;
A ceDNA vector according to any one of claims 1 to 5 .
前記隣接するITRの一方が野生型ITRでないか、又は前記隣接するITRの両方が野生型ITRでない;
前記隣接するITRが、異なるウイルス血清型に由来する;
前記隣接するITRの一方又は両方が、AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9、AAV10、AAV11、及びAAV12からなる群から選択されるAAV血清型に由来する;
前記隣接するITRが、表2に示されるウイルス血清型のいずれかの対からなる群から選択される;及び/又は
前記隣接するITRの一方又は両方が、表3に示される配列のうちの1つ以上からなる群から選択される配列を含む、
請求項1~7のいずれか一項に記載のceDNAベクター。 one of the flanking ITRs is a wild-type ITR or both of the ITRs are wild-type ITRs ;
one of the flanking ITRs is not a wild-type ITR or both of the flanking ITRs are not wild-type ITRs;
the flanking ITRs are from different viral serotypes;
one or both of the flanking ITRs are derived from an AAV serotype selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, and AAV12;
the flanking ITRs are selected from the group consisting of any pair of viral serotypes shown in Table 2; and/or
One or both of the flanking ITRs comprises a sequence selected from the group consisting of one or more of the sequences shown in Table 3 .
A ceDNA vector according to any one of claims 1 to 7 .
前記隣接するITRの一方又は両方が、前記B及びB’領域によって形成されるステムループ構造の全部又は一部の欠失をもたらす、欠失、挿入、及び/又は置換によって修飾されている;
前記隣接するITRの一方又は両方が、前記C及びC’領域によって形成されるステムループ構造の全部又は一部の欠失をもたらす、欠失、挿入、及び/又は置換によって修飾されている;
前記隣接するITRの一方又は両方が、前記B及びB’領域によって形成されるステムループ構造の全部又は一部、並びに/又は前記C及びC’領域によって形成されるステムループ構造の全部又は一部の欠失をもたらす、欠失、挿入、及び/又は置換によって修飾されている;
野生型ITRにおいて、前記隣接するITRの一方又は両方が、前記B及びB’領域によって形成される第1のステムループ構造と、前記C及びC’領域によって形成される第2のステムループ構造とを含む領域に、単一のステムループ構造を含む;
野生型ITRにおいて、前記隣接するITRの一方又は両方が、前記B及びB’領域によって形成される第1のステムループ構造と、前記C及びC’領域によって形成される第2のステムループ構造とを含む領域に、単一のステム及び2つのループを含む;及び/又は
野生型ITRにおいて、前記隣接するITRの一方又は両方が、前記B及びB’領域によって形成される第1のステムループ構造と、前記C及びC’領域によって形成される第2のステムループ構造とを含む領域に、単一のステム及び単一のループを含む、
請求項1~10のいずれか一項に記載のceDNAベクター。 one or both of the flanking ITRs are modified by a deletion, insertion, and/or substitution in at least one of the ITR regions selected from the group consisting of A, A', B, B', C, C', D, and D' regions ;
one or both of the flanking ITRs are modified by deletion, insertion, and/or substitution, resulting in the loss of all or part of the stem-loop structure formed by the B and B'regions;
one or both of the flanking ITRs are modified by deletions, insertions, and/or substitutions that result in the loss of all or part of the stem-loop structure formed by the C and C'regions;
one or both of the flanking ITRs are modified by deletion, insertion, and/or substitution resulting in the loss of all or part of the stem-loop structure formed by the B and B' regions and/or all or part of the stem-loop structure formed by the C and C'regions;
in the wild-type ITR, one or both of the flanking ITRs contain a single stem-loop structure in a region that includes a first stem-loop structure formed by the B and B' regions and a second stem-loop structure formed by the C and C'regions;
in the wild-type ITR, one or both of the flanking ITRs comprise a single stem and two loops in a region that comprises a first stem-loop structure formed by the B and B' regions and a second stem-loop structure formed by the C and C'regions; and/or
In the wild-type ITR, one or both of the flanking ITRs contain a single stem and a single loop in a region that contains a first stem-loop structure formed by the B and B' regions and a second stem-loop structure formed by the C and C' regions .
A ceDNA vector according to any one of claims 1 to 10 .
A kit comprising a ceDNA vector according to any one of claims 1 to 18 , a composition according to claim 28 , or a cell according to claim 29 , together with instructions for use .
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2021
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- 2021-03-24 CN CN202180037433.2A patent/CN115667530A/en active Pending
- 2021-03-24 MX MX2022011805A patent/MX2022011805A/en unknown
- 2021-03-24 KR KR1020227036899A patent/KR20230003477A/en unknown
- 2021-03-24 AU AU2021244555A patent/AU2021244555A1/en active Pending
- 2021-03-24 CA CA3172572A patent/CA3172572A1/en active Pending
- 2021-03-24 EP EP21719390.3A patent/EP4127187A1/en active Pending
- 2021-03-24 JP JP2022557749A patent/JP2023520764A/en active Pending
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