A scalable platform for exon-skipping antisense oligonucleotide therapy development for inborn genetic diseases

High-throughput in silico prediction of exon dispensability with automated design of antisense oligonucleotides skipping the variant-carrying exon, illustrated by preserved protein function after skipping a dispensable exon of SOX5.

Antisense oligonucleotides can induce skipping of 'dispensable' exons carrying a pathogenic variant to restore protein amount and function, but the strategy has been studied for only a small number of genes. The authors developed a high-throughput in silico tool that assesses exon dispensability and designs the corresponding oligonucleotide sequences, with parameters optimised on known dispensable and in-frame indispensable exons. Across 72,644 exons of 5,057 disease genes they identify thousands of new candidate targets (3.4% of exons under the most stringent filters, 24.5% under looser filters), collectively covering 0.97% to 15.6% of disease-causing variants listed in large-scale databases. Predictions and optimised sequences are released in the HAWK-EYE database, available as an open-access web application. A subset of sequences was experimentally validated, with skipping of a dispensable exon in SOX5 preserving protein function in in vitro and in vivo assays.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The concrete contribution is to turn a case-by-case question, is this variant amenable to exon skipping, into a simple database lookup, which helps when discussing an n-of-1 programme with a family. Perspective is needed: predicted dispensability is not demonstrated dispensability, functional validation covers SOX5 only, and moving from a theoretical target to an administrable oligonucleotide remains the real bottleneck. This is also a preprint, not peer reviewed at this stage.

Analysis by Dr Thibaut Benquey