OpenASO: RNA Rescue - designing splice-modulating antisense oligonucleotides through community science

Area of Science:

• RNA therapeutics
• Antisense oligonucleotide technology
• Computational biology

Background:

• Splice-modulating antisense oligonucleotides (ASOs) are emerging as a therapeutic strategy for genetic disorders.
• Previous ASO discovery for hemophilia A targeting F8 exon 16 was laborious and costly.
• Developing efficient methods for ASO discovery is crucial for advancing RNA-based medicine.

Purpose of the Study:

• To introduce an alternative paradigm for discovering splice-modulating ASOs using RNA structure prediction and community science.
• To evaluate the efficacy of ASOs designed through a crowdsourcing platform (Eterna OpenASO challenge) for a splicing-deficient F8 exon 16 variant.
• To demonstrate the potential of citizen science in accelerating ASO drug discovery.

Main Methods:

• Integrated data-driven RNA structure prediction with a community science approach.
• Utilized a splicing-deficient pathogenic variant of F8 exon 16 as a model system.
• Analyzed ASOs designed by citizen scientists in the Eterna OpenASO challenge for their impact on exon splicing.

Main Results:

• 25% of top-scoring ASOs designed via crowdsourcing significantly enhanced F8 exon 16 splicing.
• Combinations of ASOs designed by Eterna players showed additive effects in improving splicing efficiency.
• The crowdsourced approach identified potent splice-modulating ASOs more efficiently than conventional methods.

Conclusions:

• Crowdsourcing ASO designs through citizen science can accelerate the discovery of splice-modulating therapeutics.
• This integrated approach holds promise for developing novel RNA-based treatments for human diseases like hemophilia A.
• Community science platforms offer a scalable and cost-effective solution for identifying effective ASO candidates.