Inherited retinal degeneration: Updates in diagnosis and gene therapy

Inherited retinal degenerations (IRDs) are a group of retinal diseases that can present at any age, affect vision progressively, and remain more or less untreatable. With the advent of modern genetic technologies, it has become possible to characterize the human genome and disease-causing genes. IRDs are responsible for visual impairment and blindness in the working-age population, affecting almost 2 million people globally, over 1 in 3000 people in the UK, around 1 in 372 in rural India and 1 in 930 in urban India.[1,2] The Indian prevalence appears much higher than the West. Moreover, in India, the burden of IRDs is disproportionate to the amount of research being performed in this area.[3] The onset of disease varies in age for different IRDs, with patients suffering from progressive deterioration of their peripheral and/or central vision over several decades.[4] Therefore, it is important to identify the causative gene and variant responsible for the disease phenotype, so that targeted gene therapy if and when available can be offered to them.[5,6] This information also helps in prognostication and managing expectations throughout the patients’ lifetime. Mutations in more than 300 genes have been reported to be associated with IRDs. The genetic testing cost in India can range anywhere between INR 15000–30000, depending on whether a panel testing method or whole genome testing is conducted, the number of genes tested, family members tested other than the proband, method of high throughput computational analysis and gene variant calling, among others. Gene testing methods commonly used are gene panel testing, whole exome sequencing, whole genome sequencing via next-generation sequencing, or Sanger sequencing. There may be delays and roadblocks at each level of testing, starting from the initial detection of the eye condition, to getting a specialist referral, electrodiagnostics to narrowing down of provisional diagnosis, and then finally genetic counseling and sample collection for testing. In India, another big limiting factor towards testing is financial restriction from the family, which is often the scenario, commonly in rural settings as well as urban. Artificial intelligence (AI) has been proposed as an alternative to genetic testing for characterization of IRDs. AI models have been developed for the detection and studying the progression of IRDs like retinitis pigmentosa and Stargardt disease (STGD).[7-10] The Eye2Gene project by UCL, London researchers has been developed to predict causative genes from autofluorescence fundus imaging and optical coherence tomography features.[11] The Eye2Gene algorithm can predict the 36 most common IRD genes to a top-5 accuracy of more than 80%, with performance similar to a panel of human expert graders on an external dataset.[12-14] AI models can also help in deciding cell and gene therapy targets. For viral-based therapies, AI algorithms can predict target sites of CRISPR that offer increased efficiency of editing. A single-cell AAV engineering pipeline (scAAVengr), which is a computational platform has been designed to decide the best AAV vector for delivering gene therapy to specific parts of the retina, and this has the potential to speed up a much-prolonged process.[15] Several clinical trials are currently available for individuals with inherited retinal degenerations (IRDs), including LCA/EOSRD, using different approaches [Table 1].Table 1: Summary of different approaches to gene therapy and the products under development for several IRDs and their associated genesThe various strategies developed for gene therapy are gene supplementation, gene-editing and post-transcriptional regulation, visual cycle modulators as pharmacotherapy, and optogenetics or gene agnostic approach. Viral vector-driven gene therapy is now time-tested and has been shown to safely work; however, it is unknown how long it will persist. It is unclear as of now which is the best method to target genes for treatment, however, most likely gene editing is going to be the dominant method in future; although at this point, it is understandably not as robust for therapeutic use as we would want it to be, and there is a concern over carcinogenicity.[16,17] The future of gene therapy looks very promising depending on the perfection of delivery methods, vector design, gene agnostic therapies, scalable manufacturing, and cost-effective methods of implementation of treatment strategies.