Inherited retinal diseases (IRDs) comprise a heterogeneous group of genetic disorders affecting the retina. Caused by mutations in over 300 genes, IRDs result in visual impairment due to dysfunction and degeneration of photoreceptors, retinal pigment epithelium, or the choroid. Important photoreceptor IRDs include retinitis pigmentosa and Leber congenital amaurosis. Macular dystrophies include Stargardt and Best disease. Currently, IRDs are largely incurable but the landscape of treatment options is rapidly changing for these diseases which, untreated, result in severe visual impairment and blindness. Advances in DNA delivery to the retina and improved genetic diagnosis of IRDs have led to a new era of research into gene therapy for these vision-threatening disorders. Gene therapy is a compelling approach due to the monogenic nature of most IRDs, with the retina being a favourable target for administering genetic vectors due to its immunoprivileged environment, direct visibility, and multiple methods to assess sensitivity and function. Generally, retinal gene therapy involves a subretinal or intravitreal injection of a viral vector, which infects target cells to deliver a therapeutic gene, or transgene. A gene augmentation strategy introduces a functioning copy of a gene to restore expression of a mutated gene, whereas a gene-editing strategy aims to directly edit and correct the mutation. Common delivery vectors include adeno-associated virus (AAV) and lentivirus. Voretigene neparvovec-rzyl (Luxturna) became the first FDA-approved direct gene therapy in December 2017, and the Australian TGA followed suit in August 2020. More are projected to follow, with clinical trials underway for many other IRDs. This review provides an overview of gene therapy for IRDs, including current progress and challenges. A companion article in this issue details target patient populations for IRD gene therapy, and how optometrists can assist in assessing individuals who may be eligible for current and future therapies.

Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer’s disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.

This review presents the phenotypic and genotypic profiles of a select group of inherited retinal diseases (IRDs) that are currently the focus of retinal gene therapy trials globally. Research progress in IRD treatment trials may soon lead to their availability in Australia and New Zealand, as either approved treatment or a clinical trial. The salient clinical characteristics of retinitis pigmentosa—the largest IRD category—are highlighted, with specific reference to RPE65-associated Leber congenital amaurosis, followed by other specific IRDs, namely choroideremia and ABCA4-associated Stargardt disease. These IRDs are selected based on their candidacy for gene therapy. Guidance on the clinical diagnostic tests that support each of these diagnoses will be presented. More broadly, the most useful structure and function measures to monitor IRD progression is discussed, along with the key assessments that offer differential diagnostic insight. This review is intended to be a clinical guide for optometrists, to assist in assessment and management of individuals who may be eligible for current and future gene therapies. A companion article in this issue will provide an overview of the basic principles of gene therapy and its development as a new treatment for inherited retinal diseases.