Screening rare genetic diagnoses for amenability to bespoke antisense oligonucleotide therapy development: a retrospective cohort study

Abstract

PurposeTo estimate the proportion of molecular genetic diagnoses in a real-world, phenotypically heterogeneous patient cohort that are amenable to antisense oligonucleotide (ASO) treatment. MethodsWe retrospectively applied the N=1 Collaboratives VARIANT (Variant Assessments towards Eligibility for Antisense Oligonucleotide Treatment) guidelines to all diagnostic variants found by clinical genome-wide sequencing at a single pediatric hospital in 532 patients over a 6-year period. Variants were classified as either "eligible", "likely eligible", "unlikely eligible", or "not eligible" in relation to the different ASO approaches, or "unable to assess". ResultsIn total, 25 unique variants across 26 patients (4.9% of 532 patients) were eligible or likely eligible for ASO treatment at a molecular genetic level, via canonical exon skipping (4), splice correction (3), or mRNA knockdown (18). Only eight of these molecular genetic diagnoses were made within a year of symptom onset. After considering disease and delivery related factors, 11 diagnoses were still considered candidates for bespoke ASO development. ConclusionA meaningful proportion of genetic diagnoses identified by genome-wide sequencing may be amenable to ASO treatment. These results underscore the importance of timely diagnosis, and the proactive identification and accelerated functional testing of genetic variants amenable to ASO treatments.