(M1030-02-07) Review of First-in-Human Trials for Gene Therapy in Ocular Diseases

Purpose: The concept of gene therapy refers to using genetic methods to treat human diseases either by delivering a functional copy of the flawed gene, its correction, or treating the signs of disease impairments (1). Continuous gene expression for lifetime following a single administration is a major advantage of gene therapy which allows for maintaining a therapeutic response. Since the 1980s, gene therapy products have been tested for different diseases, however, the eye is an attractive target due to the following key characteristics: fewer vector particles or lower dose due to its size, easily accessed for different ocular routes of administration (ROA), potentially a weak immune response upon viral vector administration, and decreased systemic effects due to being substantially compartmentalized (2). Designing clinical trials for gene therapy given the novelty of it can be challenging. The purpose of this work is to review the existing first-in-human clinical trials on ocular gene therapy with emphasis on key components, such as dose, ROA, and vector system. The aim is to give insights into the improvement of clinical studies in the future for ocular gene therapy in early-stage.

Methods: This review focused on Phase 1 to 2, first-in-human (FIH), adeno-associated virus (AAV)-based gene therapy clinical trials registered in ClinicalTrials.gov for ocular disorders up to year 2023, retrospectively, with no restriction on the starting date. In this review, key trial components, such as indication, mechanism of action, dose, sample size, inclusion and exclusion criteria, and safety and efficacy outcomes were highlighted. Moreover, wherever applicable, pharmacokinetic, biodistribution, and immunogenicity data were captured.

Results: Table 1 shows a summary of ten representative clinical trials with key study design characteristics. A total of 61 studies conducted between the years 2014 to 2023 were included in this review. 17 studies were Phase I, 8 were Phase II, and 36 were Phase I/IIa. In total, there were 3 main ROAs (subretinal, intravitreal, suprachoroidal), with subretinal being the most commonly administered route (39 (63%)). Most trials used AAV2 serotype (34 (56%)). Neovascular age-related macular degeneration (nAMD) was the most studied indication followed by retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). Among three main approaches of gene therapy (gene replacement, anti-angiogenetic, and optogenetics), gene replacement was used in 34 (56%) of trials. The dose range for different ROAs were 10⁹-10¹² vector genomes (vg)/eye, 10⁸-10¹² vg/eye, and 10¹¹-10¹² vg/eye for subretinal, intravitreal, and suprachoroidal administrations, respectively. Overall, for early-phase and FIH studies, evaluating the safety of the drug product, and investigating early signs of efficacy were the primary objectives.

Conclusion: Since the approval of the first gene therapy product for LCA, it is anticipated that investment in gene therapies for ocular diseases will continue to grow. Overall, this review provides an insight into key study design characteristics and highlights the learnings from recent FIH clinical trials to inform on the successful future development of ocular gene therapy products.

References: 1. Gyles C. The promise of gene therapy. The Canadian Veterinary Journal. 2018 Jun;59(6):571.
2. Botto C, Rucli M, Tekinsoy MD, Pulman J, Sahel JA, Dalkara D. Early and late stage gene therapy interventions for inherited retinal degenerations. Progress in Retinal and Eye Research. 2022 Jan 1;86:100975.

Acknowledgements: This work has previously been submitted to and accepted by ARVO 2024 conference but was withdrawn before publishing in the journal, due to a schedule conflict.
Disclosures: All authors are employees of AbbVie and may own AbbVie stock. AbbVie sponsored and funded the study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication.


Summary of ten clinical trials’ characteristics.