Autosomal dominant retinitis pigmentosa with toxic gain of function: Mechanisms and therapeutics

Abstract

Autosomal dominant retinitis pigmentosa is a form of retinitis pigmentosa, an inherited retinal degenerative disorder characterized by progressive loss of photoreceptors eventually leading to irreversible loss of vision. Mutations in genes involved in the basic functions of the visual system give rise to this condition. These mutations can either lead to loss of function or toxic gain of function phenotypes. While autosomal dominant retinitis pigmentosa caused by loss of function can be ideally treated by gene supplementation with a single vector to address a different spectrum of mutations in a gene, the same strategy cannot be applied to toxic gain of function phenotypes. In toxic gain of function phenotypes, the mutation in the gene results in the acquisition of a new function that can interrupt the functioning of the wildtype protein by various mechanisms leading to cell toxicity, thus making a single approach impractical. This review focuses on the genes and mechanisms that cause toxic gain of function phenotypes associated with autosomal dominant retinitis pigmentosa and provide a bird’s eye view on current therapeutic strategies and ongoing clinical trials.