Selective Targeting of ATP1A3-E815K with Antisense Oligonucleotides

Antisense oligonucleotides (ASO) have emerged as effective therapeutic tools in genetic disorders of the nervous system.1-3 One strategy utilizing this technology seeks to reduce messenger RNA (mRNA) levels of a heterozygous ‘toxic’ gain-of-function variant to prevent expression of the disease-causing allele.4 Conceptually, this same approach may work for a dominant-negative variant if the wild-type (WT) allele alone can encode sufficient levels of the protein for normal physiology. ASO target mRNA in a sequence-specific manner and enable degradation of the target by ribonuclease H (RNase H1) in cells.5 The major challenge inherent in applying this therapeutic technology in a heterozygous condition is achieving specificity for the variant allele. Specificity is largely dictated by mRNA sequence and must be determined empirically. Various ASO design features including backbone chemistry can affect efficiency of targeting either the variant or WT allele, and this also requires an empiric approach.6