There are high hopes for gene therapy for LCA10, a more common genetic variant of Leber congenital amaurosis than the biallelic RPE65 mutation approved for treatment with Spark/Roche’s voretigene neparvovec, or Luxturna.
Clustered regularly interspersed palindromic repeat (CRISPR) gene editing uses a single strand guide RNA to find a host cell DNA strand of interest (CEP290 mutation, which encodes for a faulty cellular ciliary protein important to cellular microtubule formation and signaling from outer to inner photoreceptor segments). An enzyme that travels with the CRISPR guide mRNA, Cas9, then splices out the target DNA to allow DNA “gene editing” with a new DNA strand and potentially functional CEP290 cilia protein. CRISPR gene editing therefore differs from replacement gene therapy; both, however, require subretinal surgical delivery. Other approaches for LCA10 include modifications of CEP290 RNA splicing with antisense oligonucleotides (ProQR) and “mini gene” strategies for LCA10 (Iveric).
Gene therapy approaches for retinal diseases such as LCA, and even more common diseases such as neovascular age-related macular degeneration, continue to lead the way for specific FDA-approvable interventions and, more generally, proof of concept for gene therapy strategies for human disease. This Allergan-Editas LCA10 clinical trial is a watershed moment for the CRISPR gene editing approach of gene therapy.
Allen C. Ho, MD, FACS
OSN Retina/Vitreous Board Member
Disclosures: Ho reports he is a consultant to and receives grants from Allergan and ProQR.