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

Area of Science:

• RNA Therapeutics
• Genetics
• Bioinformatics

Background:

• Splice-modulating antisense oligonucleotides (ASOs) are emerging RNA-based therapeutics for human diseases.
• Traditional methods for discovering splice-modulating ASOs are resource-intensive and time-consuming.
• Previous work identified ASOs targeting intronic RNA structures to correct pathogenic variants of F8 exon 16 in hemophilia A.

Purpose of the Study:

• To develop a novel, efficient approach for discovering splice-modulating ASOs by integrating RNA structure prediction and citizen science.
• To evaluate the efficacy of ASOs designed through a crowdsourcing platform in enhancing the splicing of a deficient F8 exon 16 variant.

Main Methods:

• Utilized data-driven RNA structure prediction algorithms.
• Leveraged a community science platform (Eterna OpenASO challenge) for ASO design.
• Assessed the impact of designed ASOs on F8 exon 16 splicing in a cellular model.

Main Results:

• 25% of top-ranked ASOs designed by citizen scientists significantly improved exon 16 splicing.
• Combinations of ASOs designed by Eterna players demonstrated additive effects in enhancing splicing efficiency.
• The crowdsourced approach successfully identified functional splice-modulating ASOs.

Conclusions:

• Crowdsourcing ASO design through citizen science offers a promising strategy to accelerate the discovery of novel RNA-based therapeutics.
• This approach can complement traditional methods, potentially reducing costs and time in drug development for genetic disorders.
• The findings support the use of community science in advancing precision medicine and treating human diseases like hemophilia A.