Therapy in Rhodopsin-Mediated Autosomal Dominant Retinitis Pigmentosa

Abstract

Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP) is a hereditary degenerative disorder in which mutations in the gene encoding RHO, the light-sensitive G protein-coupled receptor involved in phototransduction in rods, lead to progressive loss of rods and subsequently cones in the retina. Clinical phenotypes are diverse, ranging from mild night blindness to severe visual impairments. There is currently no cure for RHO-adRP. Although there have been significant advances in gene therapy for inherited retinal diseases, treating RHO-adRP presents a unique challenge since it is an autosomal dominant disease caused by more than 150 gain-of-function mutations in the RHO gene, rendering the established gene supplementation strategy inadequate. This review provides an update on RNA therapeutics and therapeutic editing genome surgery strategies and ongoing clinical trials for RHO-adRP, discussing mechanisms of action, preclinical data, current state of development, as well as risk and benefit considerations. Potential outcome measures useful for future clinical trials are also addressed.

Keywords: CRISPR; autosomal dominant retinitis pigmentosa; gene therapy; genome editing; retinitis pigmentosa.

Graphical abstract

Figure 1

Gene Therapy Strategies for Autosomal Dominant Diseases Top: in autosomal dominant disorders such as RHO-adRP, one mutated copy of gene encodes the abnormal mRNA and protein (red) sufficient to cause disease. The wild-type copy is shown in green. Middle: allele-specific therapeutics target the mutated RHO gene or its mRNA product without affecting the wild-type copy. Bottom: mutation-independent therapeutics disrupt both the mutated and wild-type RHO genes or their RNA products and replace them with an exogenous copy of the codon-modified CRISPR or RNAi resistant RHO gene (blue).