Inherited retinal diseases: Therapeutics, clinical trials and end points—A review

Abstract

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders characterised by photoreceptor degeneration or dysfunction. These disorders typically present with severe vision loss that can be progressive, with disease onset ranging from congenital to late adulthood. The advances in genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRDs, with the first approved gene therapy and the commencement of multiple clinical trials. The scope of this review is to familiarise clinicians and scientists with the current management and the prospects for novel therapies for: (1) macular dystrophies, (2) cone and cone‐rod dystrophies, (3) cone dysfunction syndromes, (4) Leber congenital amaurosis, (5) rod‐cone dystrophies, (6) rod dysfunction syndromes and (7) chorioretinal dystrophies. We also briefly summarise the investigated end points for the ongoing trials.

CRB1-Associated Retinal Dystrophies: A Prospective Natural History Study in Anticipation of Future Clinical Trials

“…53,54,55 A potential method is the use of adaptive optics, as it allows for the assessment of photoreceptor viability on a cellular level, which, in turn, can shed light on their amenability for gene therapy treatment. 55,56,57 It would be of great interest to assess in future studies whether photoreceptors can be adequately identified using adaptive optics considering the severe, early-onset degeneration and the characteristic retinal phenotype seen in CRB1 patients.…”

The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease

“…These discs are phagocystosed by RPE cells and result in the production of toxic bis-retinoids such as N-retinylidene-N-retinylethanolamine (A2E) and lipofuscin, ultimately leading to RPE atrophy, photoreceptor degeneration, and permanent vision loss [54,55]. Multiple clinical trials are targeting different steps in the vitamin A cycle as a potential therapy for Stargardt disease [56]. ALK-001, a deuterated form of vitamin A (C20-D3-vitamin A), was shown in a murine model to slow down the rate of vitamin A dimerization without affecting retina function [57] and is currently being evaluated in a Phase 2 clinical trial (NCT02402660, Alkeus Pharmaceuticals).…”

“…ALK-001, a deuterated form of vitamin A (C20-D3-vitamin A), was shown in a murine model to slow down the rate of vitamin A dimerization without affecting retina function [57] and is currently being evaluated in a Phase 2 clinical trial (NCT02402660, Alkeus Pharmaceuticals). Fenretinide, LBS-008, STG001 (NCT04489511, Stargazer Pharmaceuticals), and A1120 are other novel therapeutics that have been shown in preclinical models to selectively deplete vitamin A from the eye through competitive inhibitory mechanisms on retinal binding protein-4 (RBP-4) [56,58]. Emixustat is a small molecule that targets the RPE65 enzyme to reduce the production of the visual chromophores (11-cis-retinal) from vitamin A, thereby reducing the accumulation of toxic A2E and lipofuscin [54].…”

Immunologic Rejection of Transplanted Retinal Pigmented Epithelium: Mechanisms and Strategies for Prevention

“…Retinal diseases with degeneration or dystrophy of photoreceptors are visually devastating and there are no current therapies to regenerate retinal tissue. In age-related macular degeneration (AMD) and some forms of inherited retinal diseases (IRDs) such as Best Disease and MERTK-associated Retinitis Pigmentosa (RP), the primary dysfunction affects the retinal pigmented epithelium (RPE) (1)(2)(3). Adjacent to the neuroretina, the RPE is responsible for supporting the metabolism of lightsensing photoreceptors, regenerating 11-cis-retinol for the visual cycle, forming the outer bloodretinal barrier, and reducing light scatter (4).…”

“…Adjacent to the neuroretina, the RPE is responsible for supporting the metabolism of lightsensing photoreceptors, regenerating 11-cis-retinol for the visual cycle, forming the outer bloodretinal barrier, and reducing light scatter (4). Degeneration of RPE leads to secondary loss of photoreceptors and subsequent permanent loss of vision (2,3). The latest research seeks to treat these degenerative conditions by transplanting healthy RPE at early stages of disease.…”