Molecular Therapies for Inherited Retinal Diseases-Current Standing, Opportunities and Challenges

Abstract

Inherited retinal diseases (IRDs) are both genetically and clinically highly heterogeneous and have long been considered incurable. Following the successful development of a gene augmentation therapy for biallelic RPE65-associated IRD, this view has changed. As a result, many different therapeutic approaches are currently being developed, in particular a large variety of molecular therapies. These are depending on the severity of the retinal degeneration, knowledge of the pathophysiological mechanism underlying each subtype of IRD, and the therapeutic target molecule. DNA therapies include approaches such as gene augmentation therapy, genome editing and optogenetics. For some genetic subtypes of IRD, RNA therapies and compound therapies have also shown considerable therapeutic potential. In this review, we summarize the current state-of-the-art of various therapeutic approaches, including the pros and cons of each strategy, and outline the future challenges that lie ahead in the combat against IRDs.

Keywords: DNA therapies; IRD; RNA therapies; clinical trials; compound therapies; inherited retinal diseases.

Figure 1

Schematic representation of potential therapeutic approaches according to the retinal disease progression and the knowledge of the genetic cause of the retinal disease. Genetic therapies (blue boxes) are preferred in the first steps of the disease progression (retinal cells are still alive) and when knowledge of the genetic causes of the diseases is present. As the disease progresses and the knowledge of the pathogenesis decreases, other approaches such as cell therapies (pink box) or retinal prosthetic implants (yellow box) can be used. Compound therapies (black box), based on pharmacological treatments, could be used as an alternative approach when the genetic cause of the disease or the pathway involved are either known or unknown. For late-stage diseases, optogenetics or retinal prostheses may be the only option. Image sources—smart.servier.com and Doheny Retina Institute (new.bbc.co.uk/2/hi/science/nature/6368089).

Figure 2

Schematic and simplified representation of the several types of molecular therapies. (A) DNA therapies are represented by gene augmentation, genome editing and optogenetics. In gene augmentation, the entire coding sequence of the gene of interest (GOI) is delivered using different vectors. Genome editing employs nucleases able to edit the DNA at a specific position; CRISPR/Cas9 is depicted in green, guide RNA in dark yellow and ZFN and TALEN in blue. Mutations are depicted in red. In optogenetics, a light-sensitive molecule is delivered to the eye to give photosensitive properties to remaining retinal neurons. (B) RNA therapies; splicing modulation can be achieved using AONs (in dark blue) for (pseudo)exon skipping or modified U1 snRNA (in black) to favour exon inclusion in cases where mutations (in red) are found in the donor splice site. Trans-splicing occurs between two independent RNA molecules—The original transcript and the exogenous molecule without the mutation. In all cases, splicing is modulated to obtain a transcript with full or residual function. Post-translational gene silencing can be achieved by degrading the RNA transcript using AONs (dark blue), Cas13 (green) with a guide RNA (dark yellow) or (s)iRNA and hhRz (in green). These approaches can be used for dominant-negative mutations by promoting allele-specific degradation. Mutations are indicated in red. With RNA editing using CRISPR/Cas technology, dead Cas13 (in green) is conjugated with an adenosine deaminase (dark yellow) acting at the RNA level (ADAR, in light red). This molecule is guided to the mutation using a guide RNA binding on top of the mutation (in red) to induce a G-to-A transversion. (C) Representative examples of compound therapies. Translational read-through allows the ribosome to continue protein synthesis despite a premature stop codon (in red) in the presence of the translational read-through-inducing drugs (TRIDs). Restoring proteostasis can be accomplished by using chaperones to properly fold proteins. QLT091001 is a pathway-specific therapy that acts in the visual cycle and can be used when for example, RPE65 or LRAT are mutated.