Preclinical evaluation of antisense oligonucleotide therapy in a mouse model of-related neurodevelopmental disorder.

Abstract

Mutations incause an X-linked disorder characterized by developmental delay, intellectual disability, motor and gait disturbances, and seizures. Murine models that reproduce key clinical features of-related neurodevelopmental disorder suggest that it may result from a toxic gain of function of the mutant protein or a complex loss of normal HNRNPH2 function with impaired compensation by its paralog, HNRNPH1. In this study, we tested gapmer antisense oligonucleotides (ASOs) that target murinein a non-allele-specific manner. The lead ASO reducedmessenger RNA (mRNA) and protein expression while inducing compensatory up-regulation ofexpression in both wild-type andmutant mouse brains. A single intracerebroventricular injection of theASO into neonatal mutantmice rescued molecular and audiogenic seizure phenotypes and improved certain motor and cognitive phenotypes. ASO treatment at the juvenile stage also rescued audiogenic seizures. In contrast,ASO administration did not alter survival, body weight, or the incidence of hydrocephalus. In human induced pluripotent stem cell-derived neurons, a human-specificresearch ASO reducedmRNA and up-regulatedmRNA. Mechanistically, we found thatexpression is regulated by alternative splicing and that HNRNPH2 modulates this process. These findings provide a preclinical proof of concept forASO therapy and offer insights into its underlying molecular mechanism.