JPWO2020214987A5 - - Google Patents

Claims (30)

A pharmaceutical composition for treating one or more hallmarks of neurodegeneration or impaired cognition, comprising: a MuSK NG agonist . A pharmaceutical composition for increasing neurogenesis, comprising: a MuSK NG agonist . 3. The pharmaceutical composition of claim 1 or 2, wherein the MuSK NG agonistic agent is or comprises a small molecule , or is or comprises an antibody agent, or is or comprises an oligonucleotide . 4. The pharmaceutical composition of claim 3, wherein said antibody agent specifically binds to MuSK polypeptide or targets MuSK and specifically binds to said Ig3 domain of MuSK polypeptide. 5. The pharmaceutical composition of claim 4 , wherein said antibody targeting said Ig3 domain of MuSK protein is capable of specifically binding said Ig3 domain relative to the Igl or Ig2 domains of MuSK. A medicament according to any one of claims 3 to 5, wherein the antibody agent is a bivalent immunoglobulin molecule , or is or comprises a monoclonal antibody, or is or comprises a polyclonal antibody. composition . 4. The pharmaceutical composition of claim 3 , wherein said MuSK NG agonist is an oligonucleotide. 8. The pharmaceutical composition of claim 7 , wherein the MuSK NG agonist increases alteration of transcript splicing. 9. The pharmaceutical composition of claim 8 , wherein said altering transcript splicing is or comprises altering MuSK splicing. Said alteration of MuSK splicing may result in the production of products with desired and/or enhanced biological functions and/or the production of undesired splicing products by altering splicing products such that undesired biological functions may be suppressed. 10. A pharmaceutical composition according to claim 9 , comprising product knockdown. 10. The pharmaceutical composition of claim 9 , wherein said alteration of MuSK splicing comprises a transcript lacking a sequence encoding a MuSK Ig3 domain. 12. The pharmaceutical composition of claim 11 , wherein said product is mRNA. 10. The pharmaceutical composition of Claim 9 , wherein said alteration comprises skipping one or more exons. 14. The pharmaceutical composition of claim 13 , wherein exon skipping increases said splicing of transcripts in that it increases levels of mRNAs and proteins with enhanced beneficial activity compared to the absence of exon skipping. things . 14. The pharmaceutical composition of claim 13 , wherein exon skipping increases said splicing of transcripts in that exon skipping reduces levels of mRNAs and proteins with unwanted activities compared to the absence of exon skipping. 16. The pharmaceutical composition of claim 15 , wherein exon skipping increases said splicing of transcripts in that it reduces the levels of MuSK Ig3 domain mRNA and protein. 14. The pharmaceutical composition of claim 13 , wherein said skipped one or more exons are in said MuSK Ig3 domain. 18. The pharmaceutical composition of claim 17 , wherein said skipped exon is exon 6 of the MuSK Ig3 domain. 18. The pharmaceutical composition of claim 17 , wherein said skipped exon is exon 7 of the MuSK Ig3 domain. 18. The pharmaceutical composition of claim 17 , wherein said skipped exons are exons 6 and 7 of the MuSK Ig3 domain. 8. The pharmaceutical composition of Claim 7 , wherein said oligonucleotide comprises controlled structural elements. 18. The pharmaceutical composition of Claim 17 , wherein said oligonucleotide comprises a chemical modification. 23. The pharmaceutical composition of Claim 22 , wherein said chemical modifications comprise one or more types of base modifications, sugar modifications, and internucleotide linkage modifications. 24. The pharmaceutical composition of Claim 23 , wherein said chemical modification comprises a sugar modification. 25. The pharmaceutical composition according to claim 24 , wherein said sugar modification is a 2-MOE modification. A population of cells that has been exposed to a MuSK NG agonist, whereby the level or percentage of cells characterized by a neuronal marker is increased within the population relative to that observed without said exposure. 27. The population of claim 26 , wherein said neural marker is selected from the group consisting of Dex, Map2, GFAP, CNPase, S100b, O4, Sox2, Nestin, and combinations thereof. A method of characterizing a MuSK NG agonist comprising:
assessing the ability to reduce MuSK-Ig3-BMP complex formation;
assessing the ability to alter the splicing pattern of the primary MuSK transcript;
assessing the ability to inhibit expression of the transcript;
assessing the ability to increase expression of MuSK transcripts lacking sequences encoding said Ig3 domain;
assessing the ability to increase levels of MuSK polypeptides lacking functional Ig3; and assessing the ability to affect cell characteristics in a population. How to characterize. A genetically modified mouse comprising a sequence encoding MuSK in its genome, said sequence encoding MuSK not including the nucleotide distance from exon 6 to exon 7 (in 5′ to 3′ order) a genetically modified mouse, wherein said genetically modified mouse is incapable of expressing a full-length MuSK transcript or producing a full-length MuSK protein; 30. The genetically modified mouse of claim 29 , which is incapable of expressing a MuSK protein comprising the amino acid sequence in SEQ ID NO:2.