Diseases that affect the retina, the light-sensitive layer at the back of the eye, are a significant cause of visual impairment and blindness. Current research advances in gene therapy offer promise for treating some of these conditions, potentially transforming the therapeutic landscape for eye health. Challenges in gene therapy, however, remain regarding its safety and efficacy. Early attempts at gene therapy have shown severe adverse effects, including immune responses, undesired gene insertion leading to cancer-related genes activation, and death. Despite these challenges, improvements in delivery systems have led to significant progress in the development of gene therapies for retinal diseases.
Retinal diseases are considered ideal candidates for trials and testing of new therapies due to the easy accessibility of the retina and the limited immune response in the eyes. Gene therapy can help treat inherited retinal diseases that were previously considered untreatable, as well as acquired retinal diseases with complex origins. The development of gene therapy approaches for retinal diseases involves multiple factors such as the type of delivery system, the size of the therapeutic gene, the target retinal cell type, the immune response, and cost-effectiveness. The route of administration, such as subretinal, intravitreal, or suprachoroidal injections, is crucial in delivering gene therapy to the target tissues effectively.
Viral vector delivery systems, such as adenoviruses and adeno-associated viruses, have been used as vectors for retinal diseases due to their ability to selectively express the therapeutic gene in target tissues. Nonviral delivery systems, including nanoparticles and liposomes, are also being investigated for gene therapy due to their advantages in delivering larger DNA molecules and cost-effective manufacturing. Subretinal and intravitreal injections are commonly used to deliver vectors to the retina, targeting photoreceptors and retinal pigment epithelium. Newer approaches, such as suprachoroidal injections, are being explored for easier vector delivery and administration.
Inherited retinal diseases, caused by genetic mutations in over 300 genes, can be targeted for gene therapy. Early efforts at gene therapy for retinal diseases focused on Leber congenital amaurosis (LCA) caused by the RPE65 gene mutation, showing sustained improvements in visual function. Recent clinical trials for inherited retinal diseases caused by recessive mutations in the GUCY2D and RLBP1 genes have shown promising results in visual function improvements. Gene therapy for glaucoma, the leading cause of irreversible blindness in individuals over 60 years old, aims at reducing intraocular pressure and modulating genes involved in the loss of retinal ganglion cells.
Challenges in gene therapy for retinal diseases include the long-term safety and efficacy of the therapeutic gene, large-scale vector manufacturing, accessibility, and costs. Limited access to genetic diagnosis in developing countries and the requirement of viable target cells for gene therapy efficacy pose additional challenges. Advances in optogenetics have shown promise in making other cells light-sensitive to restore vision in degenerated photoreceptors. With ongoing clinical trials and the likelihood of more gene therapies being approved in the future, gene therapy for retinal diseases holds significant promise for improving eye health.
