| Summary: | Mutations in the <i>Crumbs homolog 1</i> (<i>CRB1</i>) 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 <i>CRB1</i>-IRDs. Therefore, it is of great interest to evaluate gene editing strategies capable of correcting <i>CRB1</i> mutations. A retrospective chart review was conducted on ten patients demonstrating one or two of the top ten most prevalent <i>CRB1</i> mutations and receiving care at Columbia University Irving Medical Center, New York, NY, USA. Patient phenotypes were consistent with previously published data for individual <i>CRB1</i> 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 <i>CRB1</i> mutation, base editing has the potential to generate harmful bystanders. Prime editing, however, avoids these bystanders, highlighting its future potential to halt <i>CRB1</i>-mediated disease progression. Additional studies investigating prime editing for <i>CRB1</i>-IRDs are needed, as well as a thorough analysis of prime editing’s application, efficiency, and safety in the retina.
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