Scaling haplospecific antisense oligonucleotides from N-of-1 to broad use in genetic disease populations by diplotyping.

Four haplospecific antisense oligonucleotides targeting SCN2A SNP-tagged haplotypes provided coverage for 76.2% of 1,000 Genomes Project subjects, enabling scalable N-of-1 applications.

• Why it matters: The accelerated FDA N-of-1 pathway is too limited for sustainable broad use, so therapies need pre-defined haplospecific designs that fit many individuals with dominant genetic disorders.
• What they did: After N-of-1 safety and efficacy in two SCN2A-complex neurodevelopmental disorder probands, the team used whole-genome sequencing haplotyping by read proximity in 21 probands and then analyzed 1kGP haplotypes tagged by 156 SNPs.
• The result: Ten of 21 probands (48%) had ASO-eligible diplotypes, and in silico specificity and potency supported additional haplospecific ASOs validated in reprogrammed 1kGP cells heterozygous for tagging SNPs.

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