Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

Author:

Wu Kevin Y.1ORCID,Kulbay Merve2,Toameh Dana3,Xu An Qi2,Kalevar Ananda1,Tran Simon D.4ORCID

Affiliation:

1. Division of Ophthalmology, Department of Surgery, University of Sherbrooke, Sherbrooke, QC J1G 2E8, Canada

2. Faculty of Medicine, University of Montreal, Montreal, QC H3T 1J4, Canada

3. Faculty of Medicine, McGill University, Montreal, QC H3G 2M1, Canada

4. Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3A 1G1, Canada

Abstract

Retinitis pigmentosa (RP) is a heterogeneous group of hereditary diseases characterized by progressive degeneration of retinal photoreceptors leading to progressive visual decline. It is the most common type of inherited retinal dystrophy and has a high burden on both patients and society. This condition causes gradual loss of vision, with its typical manifestations including nyctalopia, concentric visual field loss, and ultimately bilateral central vision loss. It is one of the leading causes of visual disability and blindness in people under 60 years old and affects over 1.5 million people worldwide. There is currently no curative treatment for people with RP, and only a small group of patients with confirmed RPE65 mutations are eligible to receive the only gene therapy on the market: voretigene neparvovec. The current therapeutic armamentarium is limited to retinoids, vitamin A supplements, protection from sunlight, visual aids, and medical and surgical interventions to treat ophthalmic comorbidities, which only aim to slow down the progression of the disease. Considering such a limited therapeutic landscape, there is an urgent need for developing new and individualized therapeutic modalities targeting retinal degeneration. Although the heterogeneity of gene mutations involved in RP makes its target treatment development difficult, recent fundamental studies showed promising progress in elucidation of the photoreceptor degeneration mechanism. The discovery of novel molecule therapeutics that can selectively target specific receptors or specific pathways will serve as a solid foundation for advanced drug development. This article is a review of recent progress in novel treatment of RP focusing on preclinical stage fundamental research on molecular targets, which will serve as a starting point for advanced drug development. We will review the alterations in the molecular pathways involved in the development of RP, mainly those regarding endoplasmic reticulum (ER) stress and apoptotic pathways, maintenance of the redox balance, and genomic stability. We will then discuss the therapeutic approaches under development, such as gene and cell therapy, as well as the recent literature identifying novel potential drug targets for RP.

Publisher

MDPI AG

Subject

Pharmaceutical Science

Reference240 articles.

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2. (2022, December 15). Retinitis Pigmentosa: Study Guide. Available online: https://www.aao.org/Assets/bcc226cb-7ac7-443c-897e-9b20afdfacfb/637153836910470000/r38u-pdf?inline=1&fbclid=IwAR2oP_lD1pWSAROpIfa9poqhZzeSf29_PvZztBZMSQfWKNqTbv1b6t0BXJU.

3. O’Neal, T.B., and Luther, E.E. (2022). StatPearls, StatPearls Publishing.

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