Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

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.

Keywords: ER stress; gene therapy; neuroprotection; optogenetics; photoreceptor cell death; preclinical studies; retinal degeneration; retinitis pigmentosa; stem cell therapy; therapeutic target.

Figure 1

Advanced therapeutic modalities for retinitis pigmentosa. (a) Gene therapy, using virus-mediated injection of therapeutic gene to replace disease-causing gene; (b) Cell therapy, by injecting stem cells to replace injured cells and form synaptic connections with remaining retinal neurons; (c) Optogenetics, by introducing photosensitive proteins into degenerated retina to restore cone function, and (d) Neuroprotective agents, such as neurotrophic factors, anti-apoptotic agents and antioxidants, used in early stages of the disease and as adjunctive treatment. Adapted by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates (accessed on 20 January 2023).

Figure 2

Schematic illustration of phototransduction mechanism and impacts of retinitis pigmentosa pathogenesis. In rod cells, light exposure induces transducer activation and subsequent phosphodiesterase (PDE) expression. PDE induces sodium channel closure. Rhodopsin (Rhodopsin*) and cyclic nucleotide-gate (CNG) ion channel mutations (CNGB*) alter rhodopsin signalization and are involved in retinitis pigmentosa pathogenesis. The figure was adapted from [98]. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 3

Overview of photoreceptor cell death pathways and their alteration in retinitis pigmentosa. Photoreceptor cell death is mainly mediated by (1) the activation of the intrinsic apoptosis pathway through cytochrome c release, (2) endoplasmic reticulum (ER) stress pathway through the activation of IRE1a, PERK, or ATF6, and (3) through inflammasome activation in macrophages. Mutations in XX have shown to induced early photoreceptor cell death in retinitis pigmentosa, leading to vision loss. Rhodopsin mutations enhance CHOP expression. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 4

Favorable characteristics of exosomes. This Figure illustrates the favorable characteristics of exosome therapy, including its ability to target specific cells and tissues, high biocompatibility, resistance to degradation, and capacity to penetrate barriers such as the blood-retinal barrier. Adapted by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates (accessed on 20 January 2023).