Population-scale genome-wide prioritization of targets for allele-specific antisense oligonucleotide therapy design

Population-scale prioritization identified 7,927 ASO-targetable SNVs across 408 GOF/DN disease genes, achieving a median cumulative heterozygous population coverage of 88.9% in 1000 Genomes.

• Why it matters: Patient-specific SNV selection in cis may restrict ASO applicability and worsen inequities, so population-level ASO-target selection needs scalable evaluation across ancestries and datasets.
• What they did: A greedy algorithm selected ASO-targetable SNVs maximizing population coverage in 1000 Genomes superpopulation groups, then assessed replication coverage and attempted allele-specific 15-mer and 20-mer ASO design.
• The result: Coverage was consistently high across ancestries (median ≥85%) and generalized to replication datasets (median 86.4% in HGDP; 90.3% in All of Us), enabling candidate ASO generation for future validation.