Splicing alterations: from pathogenic variant discovery to next generation therapeutics development
Many human genetic diseases are associated with defects in post-transcriptional gene regulation and alternative splicing. Despite rapid technological advancements, successful diagnostic rates for rare genetic disorders are still low and clinical interventions and treatments unavailable for most patients. This project aims to address this challenge by developing novel antisense RNA therapies based on the splice-switching oligonucleotide (SSO) technology. SSOs allow correcting aberrant transcript splicing by targeting disease mutations at the transcript level. This project comprises three aims. First, discovery of candidate target genes for SSOs will involve transcriptome sequencing (RNA-seq) of patient samples and identification of potentially pathogenic genetic variants using public databases. Second, a set of SSOs for top-ranking candidates will be designed and tested experimentally in vivo in human HepG2 cell line.