Antisense oligonucleotides as a precision therapy for developmental and epileptic encephalopathies

Abstract

Developmental and epileptic encephalopathies (DEEs) comprise a complex spectrum of neurological disorders characterized by neurodevelopmental delay and early-onset seizures primarily caused by diverse genetic mutations. Traditional treatments have largely been symptomatic, focusing on seizure control without addressing the underlying genetic causes. The advent of gene therapy, particularly through antisense oligonucleotides (ASOs), offers a promising avenue toward targeted therapeutic interventions. ASOs by virtue of their ability to modulate gene expression at the mRNA level represent a sophisticated approach to counteract the effects of pathogenic mutations. This review delves into the recent advancements in ASO technology, highlighting its application in preclinical and clinical settings for DEEs. We present evidence of the efficacy of ASOs in ameliorating disease phenotypes in vitro and in vivo, alongside promising outcomes from ongoing clinical trials. The therapeutic landscape for DEEs is on the cusp of significant transformation, underscored by the potential of ASOs to offer precise, personalized, treatments that extend beyond symptomatic relief to potentially rectify the genetic underpinnings of these disorders.