Evaluating Human Mutation Databases for ‘Treatability’ Using Personalized Antisense Oligonucleotides

Genome sequencing in the clinic often allows patients to receive a molecular diagnosis. However, variants are most often evaluated for pathogenicity, neglecting potential “treatability”, and thus often yielding limited clinical benefit. Several collaborative efforts now aim to provide a therapy based upon the genetic variants, even if the drug will benefit only a single patient. Antisense oligonucleotide (ASO) therapies, among others, offer attractive “programmable” and relatively safe platforms for individualized therapy. The landscape of “ASO-treatable” variants is largely uncharted, with new developments emerging for loss-of-function (LOF), haploinsufficient, and gain-of-function (GOF) variants. ASOs can access the genome to target splice-gain variants, poison exons, untranslated/regulatory regions, and naturally-occurring antisense transcripts. Many of these approaches have yet to be proven clinically beneficial, and it is unclear if disease in some patients has progressed past the point where benefit could reasonably be expected. Here we mine public variant databases to identify potential future therapeutic targets. We found that the majority of human pathogenic genetic variants have one or more approaches that could be targeted therapeutically, advantaging the many ways that ASOs can regulate gene expression. The future might see medical teams considering “treatability” when interpreting genome sequencing results, to fully realize benefits for patients. ### Competing Interest Statement Dr. Gleeson serves on the Access to Treat Committee and Chief Medical Officer for the non-profit N-Lorem Foundation. Dr. Gleeson consults for Ionis Pharmaceutical, Inc. and Shire Pharmaceutical, Inc.