JP-2025518052-A5 -

Dates

Publication Date

20260507

Application Date

20230511

Description

Equivalents: In addition to those shown and described herein, various modifications of the invention and many further embodiments will be apparent to those skilled in the art from the entirety of this document, including references to the scientific and patent documents cited herein. The subject matter of this specification includes important information, examples, and guidance that can be adapted to the implementation of the invention in its various embodiments and equivalents. additional array In certain embodiments, for example, the following items are provided: (Item 1) Capsid proteins comprising at least one modification that results in preferential targeting of muscle tissue by adeno-associated virus (AAV) vectors, and Nucleic acid encoding the full-length MTM1 protein AAV vectors, including... (Item 2) The AAV vector according to item 1, wherein the capsid protein comprises at least one modification, which is an insertion between any two consecutive amino acids in the AAV9 capsid polypeptide at amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 704-714, or any combination thereof, or an insertion at a similar position in the AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh. 74, AAV rh. 10 capsid polypeptide. (Item 3) The AAV vector according to item 1, wherein the capsid protein comprises at least one modification, which is a substitution of amino acids 586-88 and an insertion between amino acids 588 and 589 in the AAV9 capsid polypeptide, or a substitution and insertion at a similar position in the AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh. 74, and AAV rh. 10 capsid polypeptides. (Item 4) The AAV vector according to item 1, wherein the capsid protein comprises at least one modification, which is a substitution of amino acids 586-588 and an insertion between amino acids 588 and 589 in the AAV9 capsid polypeptide, and the insertion is selected from the sequences in Tables 1-4. (Item 5) AAV contains vp1 capsid protein, vp2 capsid protein, and vp3 capsid protein. The amino acid sequence of the aforementioned vp1 capsid protein was selected from the sequences in Table 5. The amino acid sequence of the vp2 capsid protein is selected from the sequences in Table 6, and/or The AAV vector described in item 1, wherein the amino acid sequence of the vp3 capsid protein is selected from the sequences in Table 7. (Item 6) The method according to item 1, further comprising at least one modification of the capsid protein that results in a decrease in the liver affinity of the AAV vector. (Item 7) The AAV vector according to item 1, wherein the nucleic acid encoding the full-length MTM1 protein is operably linked to a muscle-specific promoter. (Item 8) The AAV vector according to item 6, wherein the muscle-specific promoter is the MHCK7 promoter. (Item 9) The AAV vector according to item 8, wherein the nucleic acid encoding the full-length MTM1 protein comprises, downstream of the muscle-specific promoter, an alternatively spliced exon cassette, the alternatively spliced exon cassette comprising an ATG start codon at its 3' end. (Item 10) The AAV vector according to item 10, wherein the exon cassette that has undergone alternative splicing contains skeletal muscle-specific exons. (Item 11) The AAV vector according to item 11, wherein the exon cassette that has undergone alternative splicing promotes the expression of the nucleic acid in skeletal muscle. (Item 12) A method for treating X-linked myotubular myopathy (XLMTM), For individuals infected with XLMTM, Capsid proteins comprising at least one modification that results in preferential targeting of muscle tissue by adeno-associated virus (AAV) vectors, and Nucleic acid encoding the full-length MTM1 protein AAV vectors containing composition containing A method comprising the step of administering a drug. (Item 13) The method according to item 12, wherein the capsid protein comprises at least one modification which is an insertion between any two consecutive amino acids in the AAV9 capsid polypeptide between amino acids 262-269, 327-332, 382-386, 452-460, 488-505, 527-539, 545-558, 581-593, 704-714, or any combination thereof, or an insertion at a similar position in the AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh. 74, AAV rh. 10 capsid polypeptide. (Item 14) The method according to item 12, wherein the capsid protein comprises at least one modification which is a substitution of amino acids 586-88 and an insertion between amino acids 588 and 589 in the AAV9 capsid polypeptide, or a substitution and insertion at a similar position in the AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV rh. 74, and AAV rh. 10 capsid polypeptides. (Item 15) The method according to item 12, wherein the capsid protein comprises at least one modification of the AAV9 capsid polypeptide, which is a substitution of amino acids 586-588 and an insertion between amino acids 588 and 589, and the insertion is selected from the se