The Therapeutic Potential of Antisense Oligonucleotides for Diseases Implicated with Aberrant RNA Splicing Events

Abstract

Recent research estimates that up to 50% of all human disease mutations lead to dysfunctions in the RNA splicing process. RNA splicing is integral in the production of functional proteins, and therefore, errors in splicing can lead to protein-alterations or a complete loss of proteins. Disruption in crucial protein functions, such as involvement in signaling pathways, transport regulation, enzymatic processes, cellular growth, and structural integrity, can contribute to the pathogenesis of disease. The increased understanding of the contribution of aberrant RNA splicing to the manifestation of disease presents the need for therapeutic approaches to combat splicing dysfunction. Splice modulating antisense oligonucleotides (ASOs) possess high potential as a therapeutic approach for circumventing aberrant splicing events with five FDA approved treatments. Previous assessments of the potential of ASOs focus on a specific category of disease or evaluate the use of ASOs through multiple mechanistic approaches; however, an overall evaluation on splicing specific ASOs has not been done. Therefore, in this thesis I aimed to evaluate the therapeutic potential of ASOs for combatting RNA splicing errors in a variety of diseases. This evaluation was conducted through a literature review of research that tested the use of ASOs on aberrant splicing events. Through this assessment came the categorization of splice modulating ASOs into five mechanistic approaches: exon skipping, exon inclusion, cryptic splice site blocking, alternative splicing variant promoting, and circumventing dysfunctional splicing protein ASOs. The findings of this assessment display the extensive potential for the multi-mechanistic use of splice modulating ASOs to address various aberrant splicing events in a wide variety of diseases.