BLOG: Despite history of challenges, gene therapy blossoming in ophthalmology
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Gene therapy has been around for decades now, but it has had a history of challenges with only a few breakthroughs.
This technology has particularly blossomed in the ocular field where it has shown to be effective in correcting genetic diseases. Gene therapy, often referred to as “gene augmentation,” or delivery of a normal copy of the diseased gene in cells affected by a disease, is often used to address recessive diseases that are usually monogenic in nature.
Therapeutic gene delivery is accomplished by encapsulating the target gene sequence in a vector. A gene therapy vector is a transport system to deliver the therapeutic gene (transgene) to a specific target cell. Today, the gene therapy vector most used in clinical development is the adeno-associated virus (AAV). Its advantages are multiple: a very low immunogenicity; generally, no integration into the host genome; a tropism (ie, affinity for specific cell types) that can be optimized using different serotypes of the virus; and a good transduction efficiency in both dividing and non-dividing cells. Additional control of the transgene expression level and tissue localization can be achieved by selecting a gene promoter with different strength or cell specificity. However, the main limitation of the use of AAV vectors is their restricted capacity of carrying large genes, which does not allow for gene augmentation in some of the most common genetic eye diseases.
Generally, monogenic recessive diseases are the most appropriate indication for AAV technology. This allows the high unmet need in ophthalmology that represents inherited retinal diseases to be addressed. In 2017, the FDA approved the first gene therapy for an ophthalmic genetic disease. After almost 10 years of clinical development, Luxturna (voretigene neparvovec, Spark Therapeutics) was approved to treat inherited retinal disease caused by mutations in the RPE65 gene. A year later, it was approved by the European Medicines Agency. The hallmarks of RPE65 disease are early onset and rapid loss of visual function; however, one of its most debilitating symptoms is the loss of light sensitivity. In its pivotal clinical trial, voretigene neparvovec showed restoration of light sensitivity, visual field, visual acuity and/or navigation in low-light environment in most subjects. Unfortunately, the complexity and challenges of retinal gene therapy have emerged this past year when pivotal clinical trials for RPGR retinitis pigmentosa and choroideremia did not meet their respective primary endpoints. This is a reminder that the development of pertinent clinical endpoints remains a challenge in ophthalmology.
Gene augmentation continues to be evaluated for the treatment of other groups of retinal diseases, including achromatopsia and retinitis pigmentosa caused by mutations in the PDE6A and RLBP1 genes, and additional trials are ongoing in RPGR retinitis pigmentosa and choroideremia. In addition, gene therapy is currently in development to address proliferative age-related macular degeneration as a way to alleviate the patient burden of repeated anti-VEGF injections.
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