Abstract: The disclosure relates to compositions and methods for treating a disease or condition associated with a TDP-pathology or a decline in TDP-43 functionality in neuronal cells in a subject, and for identifying candidate agents to restore expression of a normal full-length or protein coding STMN2 RNA.

Abstract: The present invention provides differentiated neural cells and methods for making differentiated neural cells from pluripotent stem cells (PSC) at an industrial scale sufficient for high-throughput assays. The methods of the invention allow billions of PSCs and/or neural cells differentiated from the PSCs to be cryopreserved and expanded at multiple steps.

Abstract: The invention relates to therapeutic compositions for disorders associated with haploinsufficiency. The invention provides antisense oligonucleotides useful for treating neurodevelopmental disorders associated with mutations in the SYNGAP gene. The invention provides compositions that include synthetic antisense oligonucleotides (ASOs) that promote expression of the SynGAP protein by one or any combination of (i) preventing one or more miRNAs from interfering with production of the SynGAP protein; (ii) binding to 5?-UTR of the SYNGAP1 transcript and augmenting translation of the Syngap protein; and (iii) promoting RNAseH cleavage of antisense long non-coding RNAs that are anticorrelated with SYNGAP expression. When the composition is delivered to a patient with SYNGAP haploinsufficiency, the ASOs promote expression of the SynGAP protein.

Abstract: The disclosure relates to compositions and methods for treating a disease or condition associated with a TDP-pathology or a decline in TDP-43 functionality in neuronal cells in a subject, and for identifying candidate agents to restore expression of a normal full-length or protein coding STMN2 RNA.

Abstract: The invention provides compositions useful to knock down overexpression of UBE3A and treat conditions associated with Dup15q syndrome. The compositions include antisense oligonucleotides, preferably short oligonucleotides that are complementary to, and hybridize to, UBE3A transcripts in vivo. The ASOs prevent or inhibit successful translation of UBE3A mRNA into protein. Specifically, preferred embodiments include anti-UBE3A gapmers—oligos that include a central DNA portion flanked by RNA wings. When the gapmer hybridizes to UBE3A pre-mRNA or mRNA, the duplex hybrid recruits RNaseH, which cleaves, or digests, the UBE3A pre-mRNA or mRNA, preventing expression of the UBE3A protein. Because the ASOs prevent expression of the UBE3A protein, treatment with a composition including ASOs of the disclosure may be effective to knock down overexpression of UBE3A.

Abstract: The invention relates to therapeutic compositions for disorders associated with haploinsufficiency. The invention provides antisense oligonucleotides useful for treating neurodevelopmental disorders associated with mutations in the SYNGAP gene. The invention provides compositions that include synthetic antisense oligonucleotides (ASOs) that promote expression of the SynGAP protein by one or any combination of (i) preventing one or more miRNAs from interfering with production of the SynGAP protein; (ii) binding to the 5?-UTR of the SYNGAP1 transcript and augmenting translation of the Syngap protein; and (iii) promoting RNAseH cleavage of antisense long non-coding RNAs that are anticorrelated with SYNGAP expression. When the composition is delivered to a patient with SYNGAP haploinsufficiency, the ASOs promote expression of the SynGAP protein.

Abstract: The invention relates to therapeutic compositions for disorders associated with haploinsufficiency. The invention provides antisense oligonucleotides useful for treating early-onset epileptic encephalopathy by promoting expression of Syntaxin-binding protein 1 (STXBP1). The invention provides compositions that include synthetic antisense oligonucleotides (ASOs) that prevent certain miRNAs from interfering with production of the STXBP1 protein or bind to the 5?-UTR of the STXBP1 transcript and augment translation of the STXBP1 protein. When the composition is delivered to a patient with STXBP1 haploinsufficiency, the ASOs prevent miRNA from downregulating synthesis of STXBP1 protein.

Abstract: The present invention provides differentiated neural cells and methods for making differentiated neural cells from pluripotent stem cells (PSC) at an industrial scale sufficient for high-throughput assays. The methods of the invention allow billions of PSCs and/or neural cells differentiated from the PSCs to be cryopreserved and expanded at multiple steps.

Abstract: The invention provides systems and methods for discovering candidate therapies for genetic conditions and also for screening those therapies in vitro for evidence of neurotoxicity. Where a medical condition is a consequence of a genetic target such as a mutated gene, the disclosure provides in silico methods to generate lists of candidate sequences for antisense oligonucleotides (ASOs) that will potentially bind to the gene or transcripts from the gene in vivo and treat the associated condition by restoring a healthy phenotype of gene expression. The invention provides in vitro methods for screening candidate ASO sequences for symptoms of neurotoxicity in vivo. For example, candidate sequences that are output by the in silico analytical pipeline can be synthesized and assayed against live cells in vitro.

Abstract: The invention provides therapeutic compositions that include an antisense oligonucleotide (ASO) complementary to an identified target on a Nav channel mRNA. The ASO hybridizes to its target RNA and forms a duplex that recruits RNase H to degrade the RNA, thereby downregulating Nav channel synthesis, which inhibits the neuron's ability to contribute to certain conditions such as epilepsy and pain perception. The ASO binds to one of the specific identified targets, and may be provided as a gapmer that includes a central DNA segment flanked by modified RNA wings.

Abstract: The invention provides compositions useful to knock down overexpression of UBE3A and treat conditions associated with Dup15q syndrome. The compositions include antisense oligonucleotides, preferably short oligonucleotides that are complementary to, and hybridize to, UBE3A transcripts in vivo. The ASOs prevent or inhibit successful translation of UBE3A mRNA into protein. Specifically, preferred embodiments include anti-UBE3A gapmers—oligos that include a central DNA portion flanked by RNA wings. When the gapmer hybridizes to UBE3A pre-mRNA or mRNA, the duplex hybrid recruits RNaseH, which cleaves, or digests, the UBE3A pre-mRNA or mRNA, preventing expression of the UBE3A protein. Because the ASOs prevent expression of the UBE3A protein, treatment with a composition including ASOs of the disclosure may be effective to knock down overexpression of UBE3A.

Abstract: The disclosure relates to compositions and methods for treating a disease or condition associated with a TDP-pathology or a decline in TDP-43 functionality in neuronal cells in a subject, and for identifying candidate agents to restore expression of a normal full-length or protein coding STMN2 RNA.