Researchers from the Departments of Ophthalmology, Pathology and Cell Biology, Columbia University, New York, and the Edward S. Harkness Eye Institute, New York Presbyterian Hospital, have shown that the use of CRISPR gene editing technology is capable of correcting autosomal dominant retinitis pigmentosa (ADRP) in mouse models of the disease. The researchers used a well-established strategy of gene suppression and replacement to overcome genetic heterogeneity, characteristic of retinitis pigmentosa (RP). If such technology is transferable to the clinic, the approach may be capable of tackling a large proportion of dominant RP disease without having to address individual mutations.
The genetic heterogeneity of RP is well documented in the literature with an estimated
150 different mutations been found in the rhodopsin gene alone, just one of the genes which, when mutated, may lead to RP. Approximately 30% of ADRP arises from rhodopsin mutations however, any gene therapy approach would be impractical if it had to construct a mutation specific therapy for each patient. One way to overcome this challenge is to remove all copies of rhodopsin and replace them with functioning rhodopsin genes, an idea dating back to the mid-1990s. CRISPR (an acronym for “clustered regularly interspaced short palindromic repeats”) is one of the latest gene-editing tools, originally uncovered as a bacterial defense mechanism against phage infection, and now under development as a potential gene therapy approach by multiple biotech and pharmaceutical companies worldwide.
In the current research, investigators used two AAV vectors, one comprising the CRISPR-Cas 9-guide RNA sequence to ablate all endogenous rhodopsin transcripts and a second vector comprising a replacement cDNA sequence with codon modification which escapes ablation by the CRSPR tool. The results showed that after sub-retinal injection of the ablate and replace gene sequences, the outer nuclear layer was between 17% and 36% thicker than control animals. In addition, treated animals were reported to have significantly preserved a and b waves on ERG compared to controls. Commenting on the experimental results the researchers concluded that the approach “represents a more fiscally practical strategy for overcoming the hurdle of allelic heterogeneity in different dominant disorders, especially in the field of ophthalmology. Thus, it will enable universal treatment of patients, regardless of their allelic heterogeneity.”