Neurodevelopment

Abstract

Provided herein are methods and compositions for increasing neurogenesis and for preventing or treating diseases, disorders, or conditions associated with neurodegeneration.

Claims

[Claim 1] A pharmaceutical composition for increasing neurogenesis, comprising a MuSK NG agonizing agent which is a MuSK Ig3-targeted exon-skipping oligonucleotide, A pharmaceutical composition wherein the MuSK NG agonizing agent increases the splicing modification of the MuSK transcript, and the splicing modification results in a MuSK transcript lacking the sequence encoding the MuSK Ig3 domain. [Claim 2] The pharmaceutical composition according to claim 1, wherein the modification of MuSK splicing includes the production of a product having a desired and / or improved biological function, and / or knockdown of an undesired product by modifying the splicing product so that an undesired biological function can be suppressed. [Claim 3] The pharmaceutical composition according to claim 1, wherein the product is mRNA. [Claim 4] The pharmaceutical composition according to claim 1, wherein the modification includes skipping one or more exons. [Claim 5] The pharmaceutical composition according to claim 4, wherein the splicing of the transcript is increased in such a way that exon skipping increases the levels of mRNA and protein having improved beneficial activity compared to the absence of exon skipping. [Claim 6] The pharmaceutical composition according to claim 4, wherein the splicing of the transcript is increased in such a way that exon skipping reduces the levels of mRNA and proteins having undesirable activity compared to the absence of exon skipping. [Claim 7] The pharmaceutical composition according to claim 6, wherein exon skipping increases the splicing of the transcript in such a way that it reduces the levels of mRNA and protein in the MuSK Ig3 domain. [Claim 8] The pharmaceutical composition according to claim 4, wherein the one or more skipped exons are located in the MuSK Ig3 domain. [Claim 9] The pharmaceutical composition according to claim 8, wherein the skipped exon is exon 6 of the MuSK Ig3 domain. [Claim 10] The pharmaceutical composition according to claim 8, wherein the skipped exon is exon 7 of the MuSK Ig3 domain. [Claim 11] The pharmaceutical composition according to claim 8, wherein the skipped exons are exons 6 and 7 of the MuSK Ig3 domain. [Claim 12] The pharmaceutical composition according to claim 1, wherein the oligonucleotide comprises a controlled structural element. [Claim 13] The pharmaceutical composition according to claim 1, wherein the oligonucleotide includes chemical modification. [Claim 14] The pharmaceutical composition according to claim 13, wherein the chemical modification includes one or more types of base modification, sugar modification, and nucleotide linkage modification. [Claim 15] The pharmaceutical composition according to claim 14, wherein the chemical modification includes sugar modification. [Claim 16] The pharmaceutical composition according to claim 15, wherein the sugar modification is a 2-MOE modification. [Claim 17] A population of cells that has been exposed to the MuSK NG agonizing agent described in claim 1, thereby increasing the level or percentage of cells characterized by neuronal markers within the population compared to those observed without such exposure. [Claim 18] The population according to claim 17, wherein the neuronal marker is selected from the group consisting of Dex, Map2, GFAP, CNPase, S100b, O4, Sox2, nestin, and combinations thereof. [Claim 19] A method for characterizing the MuSK NG agonizing agent described in claim 1, A step to assess the ability to reduce MuSK-Ig3-BMP complex formation; A step to assess the ability to alter the splicing pattern of the primary MuSK transcript; A step to assess the ability to inhibit transcript expression; A step of assessing the ability to increase the expression of a MuSK transcript lacking the sequence encoding the Ig3 domain; A step of assessing the ability to increase the level of a functionally deficient MuSK polypeptide; and Steps to assess the ability to influence the characteristics of cells in a population. Including one or more of the following: A method for characterizing the MuSK NG agonizing agent.

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