Genome editing for USH2A associated IRD

Mutations in the gene USH2A are the prime cause of usher syndrome in humans and results in malfunctioning of USH2A protein, impaired vision and hearing loss. In United States, approximately 15%–30% of USH2A cases are due to these mutations. Utilizing CRISPR-Cas9, Homology Independent Targeted Integration (HITI) genomic editing and gene replacement tools we are currently investigating the mechanisms by which specific mutations in genes such as USH2A and CRX lead to blinding disease. Our proposed research aims to develop a CRISPR/Cas genome editing based therapeutic approach for retinal degeneration due to mutations in the USH2A gene, which is currently an unmet clinical need for 0.5-1.8 million of people worldwide. Given the high degree of repetitive regions in usherin protein, we postulate that an usherin protein that lacks one or more of the repetitive domains, such as mutation prone exon 13 in human, may have ability to retain partial of complete gene function. If this is true, the abbreviated USH2A, lacking deleterious or mutation prone regions, will have the potential to serve as a therapeutic strategy for Usher syndrome type II by skipping the mutant exon in USH2A gene.