Seminars in Precision Medicine

Title: “Precision Genome Surgery for Imprecision Medicine”

_{This event is hosted as part of the seminar series featuring leaders in precision medicine from across the nation. Co-presented by the Center for Precision Medicine and Genomics, the Columbia Precision Medicine Initiative, and the Precision Medicine Resource of the Irving Institute for Clinical and Translational Research. This event is supported in part by a gift from Pfizer to Columbia.}

Speaker: Stephen H. Tsang, MD, PhD,  Laszlo T. Bito Associate Professor of Ophthalmology and Associate Professor of Pathology and Cell Biology.

Location: Zoom and in-person. Please register to receive the zoom link for this event.

Description: Many disorders caused by dominant mutations, including autosomal dominant forms of retinitis pigmentosa (adRP) have a profound, negative impact on health with no effective treatments. Because the dominant mutant allele produces a defective protein, these disorders cannot be treated by adding a normal copy of a gene (so-called “gene addition”). However, gene editing can directly repair a defective gene, thus providing a promising therapeutic strategy to treat adRP and other dominant disorders. An ablate-and-replace strategy where both alleles are CRISPR/Cas9-ablated and healthy CRISPR/Cas9-resistant cDNA is added.  However, shortcomings of this strategy include potential long-term transgene silencing and cDNA delivery size constraints.   With the Precision Medicine Initiative Vagelos Award, we created  a more generalized approach to dominant negative disease genes in a mutation-independent manner. To do so, we capitalize on single nucleotide polymorphism (SNP) heterozygosity to design allele-specific CRISPR/Cas9 systems. We hypothesize that SNPs can serve as targets for the selective ablation of a mutant allele while leaving the wild-type allele intact to support biological function. To test this hypothesis, we propose an SNP editing strategy targeting the highly heterozygous SNP to treat one of the most common and severe forms of rhodopsin-linked adRP (RHO­-adRP) caused by the RHO, C110R mutation.