BioProject

Dominantly inherited disorders are not typically considered therapeutic candidates for gene augmentation. More...

Dominantly inherited disorders are not typically considered therapeutic candidates for gene augmentation. Here we utilized patient iPSC-derived retinal pigment epithelium (iPSC-RPE) to test the potential of gene augmentation versus gene editing to treat Best disease, an autosomal dominant macular dystrophy caused by over 200 missense mutations. Gene augmentation restored calcium-activated chloride channel activity and improved rhodopsin degradation for a subset of dominant mutations depending on the putative role of the affected residue. In comparison, CRISPR-Cas9 editing of the mutant allele resulted in reversal of channel activity deficits for all mutations tested. Importantly, 95% of gene editing events in iPSC-RPE resulted in premature stop codons within the mutant allele, and single cell profiling demonstrated no adverse perturbation of RPE transcriptional programs. These results show that gene augmentation is a viable strategy for a subset of Best disease patients, and that non-responders are candidates for targeted editing of the mutant allele. Similar scenarios likely exist for other genotypically diverse dominant diseases, expanding the therapeutic landscape for patients. Less...