Inherited retinal degenerations (IRD) are a leading cause of blindness. Although gene-supplementation therapies have been developed, they are only available for a small proportion of recessive IRD mutations. In contrast, genome editing using CRISPR (clustered-regularly interspaced short palindromic repeats) Cas (CRISPR-associated) systems could provide alternative therapeutic avenues for treating a wide range of genetic retinal diseases through targeted knockdown or correction of mutant alleles. Progress in this rapidly-evolving field has been highlighted by recent FDA clinical trial approval for EDIT-101 (Editas Medicine Inc, Cambridge, MA, USA) which has demonstrated efficacious genome editing in a mouse model of CEP290-associated Leber congenital amaurosis and safety in non-human primates. Nonetheless, there remains a significant number of challenges to developing clinically viable retinal genome editing therapies. In particular, the heterogeneity of IRD-causing mutations in more than 200 known genes and long-term safety concerns relating to Cas9 expression in vivo. This review highlights (i) the technological advances in gene editing technology, (ii) major safety concerns associated retinal genome editing, and (iii) potential strategies for overcoming these challenges to develop clinical therapies.
Hum Gene Ther