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.

Thicknesses of the retina and choroid in children with retinitis pigmentosa

“…ADRP is a relatively mild form of RP. The gene mutations associated with ADRP can result in altered protein activity, endoplasmic reticulum dysfunction due to misfolded mutant protein molecules, mistrafficking and mislocalization of the mutant protein, and even adverse effects on the proper functioning of the wild-type protein, thus affecting the homeostasis of cells and ultimately resulting in their death [ 25 ]. ADRP includes 30 genotypes, such as RHO mutations.…”

Revisiting Retinal Degeneration Hallmarks: Insights from Molecular Markers and Therapy Perspectives

“…The most recent RP therapies involve the use of genetic tools to inhibit the causal agent and supply exogenous protein [102]. The early retinal degeneration of RP has been treated since 2018 with gene therapy, Luxturna ® , authorized by the American and European drug agencies (FDA-Food and Drug Administration and EMA-European Medicines Agency, respectively).…”

Clinical features and treatment outcomes of a patient with retinitis pigmentosa secondary to adult coats' disease

“…Typical RP is a group of hereditary degenerative diseases characterized by progressive loss of photoreceptors and RPE cells. Degeneration and apoptosis of rod photoreceptors in the peripheral retina and slowly develops to the central retina are the main causes of persistent loss of vision and eventually blindness 3 . Coats' disease is an idiopathic non-hereditary disease de ned as telangiectasia in the retina, which leads to intraretinal and subretinal exudation in the absence of vitreoretinal traction 4 .…”