- Haplospecific ASOs targeting common intronic SNPs can selectively silence disease alleles, enabling extension of N-of-1 ASO therapy to wider patient groups.
- In two SCN2A probands, haplospecific ASOs demonstrated safety and efficacy; haplotyping across 21 probands found 48% were ASO eligible.
- Population haplotype resources enable pre-design of haplospecific ASOs; four ASOs could cover 76.2% of 1kGP subjects.
Am J Hum Genet. 2026 Nov 5;113(11):2324-2341. doi: 10.1016/j.ajhg.2026.08.017.
ABSTRACT
Antisense oligonucleotides (ASOs) are versatile disease-modifying therapies for genetic diseases. An accelerated US Food and Drug Administration (FDA) pathway enables ASO treatment trial initiation in an individual within a year. However, this rapid N-of-1 pathway lacks extensibility to broad use necessary for sustainability. Individualized ASOs bind pre-mRNAs encompassing an entire locus. Thus, ASOs targeting common heterozygous polymorphisms (SNPs) are potentially haplospecific in many individuals with dominant disorders. We developed haplospecific ASOs for two probands with SCN2A-complex neurodevelopmental disorder (CND) and gain-of-function (GOF) or mixed gain-loss dysfunction (GLD) variants. The ASOs targeted reference SCN2A intronic sequences containing SNPs. The probands each had SCN2A haplotypes with reference SNP alleles in cis with causal variants and alternate SNP alleles in cis with normal mRNA. Following N-of-1 demonstration of safety and efficacy, we evaluated their applicability to 21 SCN2A-CND probands using whole-genome sequencing (WGS) with haplotyping by read proximity. Ten (48%) probands had ASO-eligible diplotypes. Haplotype analysis of unrelated 1000 Genomes Project (1kGP) participants revealed 18 additional SCN2A haplotypes present in >20% of subjects, tagged by 156 SNPs. In silico assessment of specificity and potency identified additional haplospecific ASOs for validation in reprogrammed 1kGP cells heterozygous for the tagging SNPs. A combination of four haplospecific ASOs provided coverage for 76.2% of 1kGP subjects, potentially allowing scaling of N-of-1 FDA applications in future individuals with SCN2A-CND and GOF/GLD variants. Thus, population resources have potential to prepare haplospecific ASO therapies a priori for many persons and genetic diseases, with individual ASO selection by diagnostic WGS with haplotyping.
PMID:42987799 | DOI:10.1016/j.ajhg.2026.08.017
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