Gene Therapy for Retinal Degenerative Diseases: Progress, Challenges, and Future Directions

Abstract

Since long before the first approval of gene therapy for retinal disease, ocular gene therapy has captured the hopes of patients, clinicians, and scientists alike. Indeed, the retina provides a unique system for studying and treating ocular diseases, and it holds the distinction as the first tissue targeted by an approved gene therapy for inherited disorders in the United States. There are many methods for addressing genetic diseases in the eyes using a wide range of potential delivery systems and vectors. However, despite the immense progress over the last several decades, both old and new challenges remain, such as the long-term effects of treatments, immunogenicity, targeting, and manufacturing. This review provides a discussion of the history of ocular gene therapy, the various gene therapy approaches, methods to deliver a gene directly to ocular tissues (including both routes of administration and vectors), challenges to ocular gene therapy, the current clinical trial landscape, and future directions of the field.

Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs

“…Leber congenital amaurosis (LCA) refers to a group of diseases that cause severe vision loss in infancy due to abnormal function and later degeneration of the retina. The first in vivo gene replacement therapy for an inherited disorder in the US, Luxturna® (voretigene neparvovec-rzyl, Spark Therapeutics), was approved by the FDA in 2017 for the treatment of inherited retinal dystrophy caused by biallelic RPE65 gene mutation (LCA2) 33 . This therapy, that enters a phase I trial (NCT00516477) in 2007, is based on live nonreplicating genetically modified AAV2 capsid that expresses RPE65 , delivered by a subretinal injection 34 .…”

Cell-cell interaction in the pathogenesis of inherited retinal diseases

“…Only low doses of gene therapy vectors are needed to treat the retina due to its small size and a lack of cellular proliferation in adulthood ( Trapani and Auricchio, 2018 ), and thus the risk of systemic dissemination of the vectors and immune responses is generally negligible ( Amato et al, 2021 ). In addition, surgical procedures or clinical practices have been well established to deliver the gene therapy machineries into the retina, and the therapeutic outcome can be easily monitored by ocular imaging technologies including optical coherence tomography and fundus imaging ( Drag et al, 2023 ). Therefore, gene therapy has been extensively evaluated in the retina in the past two decades.…”

“…Lentiviruses, a retrovirus with a larger packing capacity of up to 8kb, become a more compelling alternative to AAV vectors in this case. Lentiviruses pose risk of mutagenesis due to their nature to integrate into the host genome, yet such risk could be justified for treatment of the post-mitotic retina ( Drag et al, 2023 ). The initial trial of ABCA4 delivered by lentiviral vectors for treatment of Stargardt disease has showed promising safety data and the evaluation of efficacy is currently ongoing ( Parker et al, 2022 ).…”

Suprachoroidal gene transfer with nonviral nanoparticles in large animal eyes

“…A substantial number of the NPs escape from endosomes and degrade within minutes to hours, allowing expression plasmids to enter the nucleus and begin transgene expression (4)(5)(6). Relatively fast degradability of new biocompatible gene delivery materials is especially important for retinal gene therapy as recent studies have highlighted potential toxicity concerns of conventional materials, such as lipid NPs, for application in the retina (7,8). Suprachoroidal injections of PBAE NPs containing a green fluorescent protein (GFP) expression plasmid result in widespread expression of GFP in photoreceptors and retinal pigmented epithelial (RPE) cells of rats (9); however, it is important to know the extent and level of GFP expression that occurs after suprachoroidal injection of PBAE NPs in eyes that are closer in size to human eyes and that may have more substantial transport limitations.…”