Inherited retinal disorders (IRD): how could gene and cell therapy help?

Retinitis pigmentosa (RP) is a group of disorders characterized by slow, progressive cell death of the retina's light-detecting photoreceptor cells, particularly the rod cells, leading to visual impairment and, in some cases, blindness. It often causes difficulty seeing in low light (night blindness) starting in childhood, tunnel vision (loss of peripheral vision), loss of colour vision and sensitivity to bright lights. 

The exact cause of RP varies. There are over 100 different genes associated with RP. Most commonly, RP is caused by genetic changes that affect the function and survival of photoreceptor (light-sensing) cells. Mutations in these genes disrupt the normal structure or function of the retina, leading to the degeneration of photoreceptor cells. These cells, the photoreceptors, are responsible for capturing light and converting it into electrical signals for vision. The dysfunction and eventual death of these cells result in progressive loss of ability to perceive light.  

Stargardt disease is the most common form of inherited macular dystrophy. Like RP, Stargardt disease is an IRD but it affects the macula, the region of the retina which is responsible for central vision, seeing in bright light and seeing in fine detail. Damage to cells in this region typically occurs during childhood but can also have adult onset causes blurry or distorted vision. This leads to difficulties with reading, recognising faces, colour perception and seeing fine details.  

Stargardt disease is typically associated with genetic mutations that affect the function of the retinal pigment epithelium (RPE) cells and their transportation of vitamin A. The genes associated with Stargardt's are ABCA4, ELOVL4 and PROM1. Most cases of Stargardt disease are caused by mutations in ABCA4. This gene product (ABCA4 protein) is involved in recycling vitamin A during visual cycle transduction – the process by which light entering the eye is converted into an electrical signal for transmission to the brain - in the photoreceptor cells. Mutations in the ABCA4 gene prevent vitamin A recycling and lead to the accumulation of toxic byproducts, including a non-degradable waste product called lipofuscin. This builds up in the RPE cells, affecting the ability of the RPE to support the specialised photoreceptors (cone cells) in the macula. Cone cell death causes visual impairment.  

Genetic testing and counselling are crucial for diagnosing Stargardt disease and understanding its specific genetic cause (which specific mutation in the ABCA4 gene) can inform prognosis and potential treatment options. 

Variants in ABCA4 can also cause an IRD called cone-rod dystrophy.  

Gene therapy is a promising approach for treating IRDs caused by specific gene mutations. There are several approaches under development, including: 

Gene replacement/augmentation - involves delivering healthy copies of the mutated gene 

 Gene editing - modifying the mutated gene to restore its normal, healthy function 

Gene silencing – specific targeting of mutant sequences to prevent protein expression 

Modifier gene therapy – provision of a modifier gene (not the mutated gene) to restore pathways involved in disease process 

There are more than 30 gene therapies in development to treat IRDs. Several clinical trials have shown encouraging results in treating IRDs using gene therapy. However, many are still in the early stages of investigation. Challenges with delivery, appropriate timing of treatment and realistic outcome measures remain.  

One authorised gene therapy, Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics; authorised by the EMA for use in Europe in 2018), is used to treat adults and children with IRD caused by recessive mutations in the RPE65 gene. RPE65 protein is produced in RPE cells and plays an important role in vitamin A recycling during the visual cycle. When this process does not work properly, toxic waste products accumulate in the RPE affecting the health of photoreceptors. Mutations in this gene cause Retinitis Pigmentosa and Leber’s Congenital Amaurosis, a severe, early-onset IRD that leads to sight loss in childhood. LCA is a recessive condition that can arise from genetic changes in 25 genes. In 5-10% of cases, LCA results from an affected individual inheriting mutations in both copies of RPE65. These individuals may be suited for treatment with Luxturna. 

Luxturna is a one-time (per eye) gene augmentation therapy. It uses a viral vector to deliver healthy copies of the RPE65 gene to the RPE cells following subretinal injection. This injection site is between the photoreceptor cells in the retina and the RPE cells. AAV2 specifically targets RPE cells allowing functional copies of the RPE65 gene to be delivered to the cells that are initially affected in LCA. Functional RPE65 protein is made by the RPE cells. This restores the visual cycle and improves vision. Currently, this therapy can only be used when there are still a suitable number of healthy cells remaining in the retina. 

LCA, caused by mutations in the gene CEP290, is also a target for therapeutic CRISPR-Cas9 gene editing or RNA editing. These techniques can be used to block production of a mutant protein resulting from a mutation that has been identified in 77% of CEP290-LCA patients. To date, these approaches have had favourable safety profiles and promising proof-of-concept results but limited success in clinical trials. Work is ongoing to identify the patient population who will benefit most from these treatments and to determine suitable outcome measures.  

Modifier gene therapy presents an opportunity for gene-agnostic (not specific to a single gene) approaches to treating IRDs, acting to improve retinal cell health by regulating cellular pathways, including inflammation and oxidative stress, that are disrupted by disease-causing mutations. These approaches could be used to treat multiple IRDs, with clinical trials (Ocugen) currently underway for Stargardt disease, RP and geographic atrophy, the most common form of age-related macular degeneration (AMD).  

Clinical trials are ongoing to develop a gene therapy to treat Stargardt disease. These are currently in the early stages of development. A study conducted between the United States and France by the Applied Genetic Technologies Corporation (AGTC) used a viral vector to deliver a healthy copy of the ABCA4 gene to photoreceptor cells. This study, published in 2022, showed that the treatment was well-tolerated by almost all participants, but participants did not display any improvement to their vision. More research is therefore needed both to improve the delivery method, and to improve the effectiveness of the treatment. 

Stem cell therapies offer the potential for replacing damaged or lost retinal cells in IRDs. Researchers are exploring the use of pluripotent stem cells, such as induced pluripotent stem cells (iPSCs), to generate retinal cells like photoreceptors or retinal pigment epithelium (RPE) cells for transplantation. Clinical trials are underway to assess the safety and efficacy of stem cell-based therapies in treating conditions like RP and Stargardt disease. 

One promising trial, the RESCUE trial led by ReNeuron, aimed to assess the safety and efficacy of stem cell-derived retinal progenitor cells. These cells have the potential to develop into photoreceptors upon transplantation, and the hope was that they would mature and integrate into the recipient’s retina to restore their vision. Unfortunately, this first-in-human Phase I/IIa clinical trial did not live up to the high expectations. Following the report of an unsuccessful trial due to surgical complexity, limited efficacy, and in some cases worsened outcomes, ReNeuron announced in early 2022 that they would halt the development of this stem cell therapy.   

While extensive effort is being put into these stem cell therapies, the culturing of the required cells of the retina has proved more difficult and time-consuming. This means that there is still work to be done at the ‘pre-clinical’ stage of research. Once suitable protocols are established, work can progress onto clinical trials to assess the safety and efficacy of this approach in patients with retinal degenerative diseases. These stem cell therapies may seem far away; however, several research groups have obtained promising results in animal models, and the scientific community is working towards clinical trials.