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Abstract #107885 Published in IGR 23-4
Clinical and Therapeutic Evaluation of the Ten Most Prevalent Mutations
Lopes da Costa B; Lopes da Costa B; Kolesnikova M; Kolesnikova M; Levi SR; Cabral T; Tsang SH; Maumenee IH; Quinn PMJ; Quinn PMJ; Quinn PMJBiomedicines 2023; 11:
Mutations in the () gene lead to severe inherited retinal dystrophies (IRDs), accounting for nearly 80,000 cases worldwide. To date, there is no therapeutic option for patients suffering from -IRDs. Therefore, it is of great interest to evaluate gene editing strategies capable of correcting mutations. A retrospective chart review was conducted on ten patients demonstrating one or two of the top ten most prevalent mutations and receiving care at Columbia University Irving Medical Center, New York, NY, USA. Patient phenotypes were consistent with previously published data for individual mutations. To identify the optimal gene editing strategy for these ten mutations, base and prime editing designs were evaluated. For base editing, we adopted the use of a near-PAMless Cas9 (SpRY Cas9), whereas for prime editing, we evaluated the canonical NGG and NGA prime editors. We demonstrate that for the correction of c.2843G>A, p.(Cys948Tyr), the most prevalent mutation, base editing has the potential to generate harmful bystanders. Prime editing, however, avoids these bystanders, highlighting its future potential to halt -mediated disease progression. Additional studies investigating prime editing for -IRDs are needed, as well as a thorough analysis of prime editing's application, efficiency, and safety in the retina.
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