TCF4-targeting antisense oligonucleotide

TCF4-targeting antisense oligonucleotide is an investigational RNA-based therapeutic being developed for the treatment of Pitt-Hopkins syndrome (PHS). PHS is a rare neurodevelopmental disorder primarily caused by haploinsufficiency of the TCF4 gene. This antisense oligonucleotide (ASO) is designed to bind to TCF4 transcripts and increase the expression of functional TCF4 protein from the remaining healthy allele. Preclinical studies in human neural progenitor cells (NPCs) have demonstrated that these ASOs can successfully induce TCF4 mRNA and protein, activate downstream target genes such as NRXN1 and GAD45, and rescue disease-associated cellular phenotypes like proliferation defects. This approach aims to address the significant isoform diversity of human TCF4, which is not fully captured in existing animal models.