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Review
. 2023 Apr 13:11:1177838.
doi: 10.3389/fcell.2023.1177838. eCollection 2023.

Gene-agnostic approaches to treating inherited retinal degenerations

Lindsey A Chew  1   2 , Alessandro Iannaccone  1
Affiliations
Review

Gene-agnostic approaches to treating inherited retinal degenerations

Lindsey A Chew et al. Front Cell Dev Biol. .

Abstract

Most patients with inherited retinal degenerations (IRDs) have been waiting for treatments that are "just around the corner" for decades, with only a handful of seminal breakthroughs happening in recent years. Highlighting the difficulties in the quest for curative therapeutics, Luxturna required 16 years of development before finally obtaining United States Food and Drug Administration (FDA) approval and its international equivalents. IRDs are both genetically and phenotypically heterogeneous. While this diversity offers many opportunities for gene-by-gene precision medicine-based approaches, it also poses a significant challenge. For this reason, alternative (or parallel) strategies to identify more comprehensive, across-the-board therapeutics for the genetically and phenotypically diverse IRD patient population are very appealing. Even when gene-specific approaches may be available and become approved for use, many patients may have reached a disease stage whereby these approaches may no longer be viable. Thus, alternate visual preservation or restoration therapeutic approaches are needed at these stages. In this review, we underscore several gene-agnostic approaches that are being developed as therapeutics for IRDs. From retinal supplementation to stem cell transplantation, optogenetic therapy and retinal prosthetics, these strategies would bypass at least in part the need for treating every individual gene or mutation or provide an invaluable complement to them. By considering the diverse patient population and treatment strategies suited for different stages and patterns of retinal degeneration, gene agnostic approaches are very well poised to impact favorably outcomes and prognosis for IRD patients.

Keywords: gene therapy; gene-agnostic; inherited retinal degenerations; optogenetics; photoreceptor transplantation; retinal dystrophies; retinal prosthetics; stem cells.

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Conflict of interest statement

LAC has no conflicts of interest. AI is a consultant for the following, GLG Group; Teladoc Health (formerly Advance Medical, Inc.); Rhythm Pharmaceuticals; Applied Genetic Technologies Corporation; Acucela; Allergan/AbbVie; Guidepoint Clinical; 4D Molecular Therapeutics; MeiraGTX; Jannsen Pharmaceuticals; M. Arkin Ltd.; Allievex Corp; Biogen; Aldeyra Therapeutics; Clarivate Analytics; EluminexBio; IQVIA; Adverum Biotechnologies; Tegus; Twenty-Twenty; and Baker Brother Investments. AI participates on the scientific advisory boards for the following, Foundation for Fighting Blindness; the Choroideremia Research Foundation; Alia Therapeutics.

Figures

FIGURE 1
FIGURE 1
The landscape of treatment strategies for inherited retinal degenerations (IRD). Rapid acceleration of research since the 1980s has led to the discovery of 317 disease-causing genes with 281 of these genes now cloned, highlighting genotypic heterogeneity previously described by the RetNet project (hosted by the University of Texas-Houston Health Science Center) (A). The immense phenotypic heterogeneity of IRDs is further illustrated by fundus images (B, a–k). Patients with retinitis pigmentosa (RP) can present with good central retinal preservation (a–b) with mild to moderate vision loss and good preservation of the central photoreceptors exemplified by a partially detectable ellipsoid zone (EZ) and retained outer nuclear layer (ONL). However, RP can also induce significant inflammatory complications like cystoid macular edema (CME) (c). In other instances of RP, the macular area may be partially compromised (d), with minimal central EZ preservation (e). In macular, cone, and cone-rod dystrophies, central disruptions are most common, but some present with significant foveal atrophic changes and partial foveal EZ preservation (f–h); others present with global changes marked by central retinal thinning and complete EZ loss (J–K). Gene-specific therapy (C, a) is unlikely to benefit patients with severe degeneration (d–k), but gene-agnostic strategies (C, b) may still offer these patients a path to recovering vision.
FIGURE 2
FIGURE 2
Mechanisms for enhancing photoreceptor survival in early retinal degeneration. Introducing Rod-derived Cone Viability Factor (RdCVF) (A) through use of AAVs represents one potential strategy for promoting cone photoreceptor survival. The working model for this mechanism includes activation of the Basigin-1/GLUT1 complex to increase transport of glucose and potentially other similar metabolites. Proteasomal enhancement ((B) , right) to clear excess misfolded proteins represents another possible approach. This strategy could be harnessed through the discovery of small molecules or through gene augmentation for proteasomal machinery. These approaches could also be used for augmenting certain nuclear hormone receptors (like NR2E3) ((B) , left). Oral supplementation with antioxidants like N-Acetylcysteine (NAC) (C) may also support photoreceptor health, with NAC as a known scavenger of reactive oxygen species. Alternative strategies include limiting activation of microglia (D), by inhibiting excessive phagocytosis (i.e., inhibiting the TGFβ receptor), while harnessing their role in maintenance of the retina.
FIGURE 3
FIGURE 3
Stem Cell Transplantation and Regeneration. Many stem cells sources are being explored, and research efforts are focusing on streamlining regeneration methods to convert these stem cells (B) into healthy photoreceptors that can survive subretinal transplantation (scissors) while retaining light-responsive properties. Here, we highlight the origin and conversion of the following cells into photoreceptors, mesenchymal stem cells (MSCs) (A) , retinal stem cells (C) from the ciliary margin (shown by i & ii), embryonic stem cells (ESCs) (D), human induced pluripotent stem cells (hiPSCs) (E), and chemically-induced photoreceptor-like cells (CiPCs) (E) derived from fibroblasts.
FIGURE 4
FIGURE 4
Optogenetic strategies for restoring vision. In the degenerating retina (A), dying photoreceptors (iii) fail to detect light or provide the retinal interneurons with signals about visual input. Solutions include targeting retinal ganglion cells (i) with channelrhodopsins (such as ChrimsonR, blue). Another option is to target bipolar cells (ii) with GPCR opsins (purple) or to combine this approach with small molecules (red circles) that further increase light sensitivity. (B) Administration of therapy requires intravitreal delivery of AAVs mediating opsin expression in the bipolar cells and retinal ganglion cells. Use of optogenetic goggles convert digital images from a camera into light stimulation of the treated retina to support patients’ restoration of vision (C) Another possible solution is to replace dying photoreceptors with a graft of human iPSC-photoreceptors that have been transduced with optogenetic proteins like halorhodopsin.
FIGURE 5
FIGURE 5
Artificial visual prosthetic designs. Goggles with an integrated camera and transmitter (black) connected to a battery and visual processing unit (green, right side) are required for existing artificial visual prosthetics. The goggles transmit stimulation signals to (A) retinal prosthetic devices, surgical implantation (scissors) of an electrode array with a receiving coil facilitates stimulation of retinal ganglion cells (B) cortical prosthetic devices, surgical implantation of an electrode array in the primary visual cortex (V1) with a receiving coil facilitates stimulation of these cortical neurons (C) non-implanted visual prosthetics, placed on the user’s tongue contains integrated receiver for delivering electrical stimulation to the tongue (pink).
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