Insights into adeno-associated virus-based ocular gene therapy: A bibliometric and visual analysis

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TL;DR

This bibliometric analysis of 832 publications and 80 clinical trials reveals that adeno-associated virus (AAV)-based ocular gene therapy research has shifted from basic biology to clinical application, with the US leading in productivity and influence. The field is expanding beyond inherited retinal diseases to include acquired conditions like age-related macular degeneration, with "efficacy" and "safety" emerging as current research hotspots. These findings highlight the growing clinical significance of AAV-based therapies for a range of ocular diseases.

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**Background:** Gene therapy using adeno-associated virus (AAV) vectors has become a leading platform for in vivo gene delivery due to its high efficiency and safety, particularly for ocular diseases given the eye's accessibility and immune privilege. The approval of voretigene neparvovec (Luxturna) in 2017 marked a milestone. However, no comprehensive bibliometric analysis had visualized the evolution and trends of AAV-based ocular gene therapy. This study aimed to analyze research hotspots, collaborations, and future directions using bibliometric methods.

**Methods:** Publications were retrieved from the Web of Science Core Collection (WOSCC) on October 1, 2022, using a search strategy combining terms for eye/ocular diseases, AAV, and gene therapy. Inclusion criteria: English language, articles or reviews, from 1900 to October 1, 2022. After manual de-selection, 832 papers (694 articles, 138 reviews) were included. Clinical trials were identified from ClinicalTrials.gov using the term "AAV" or "AAV", yielding 80 trials. Bibliometric analysis used Microsoft Excel, CiteSpace 6.1.R3, VOS viewer 1.6.18, and an online platform. CiteSpace parameters: Time Span January 1990–September 2022, Years Per Slice = 2, Node Types included author, institution, country, keyword, category, reference, cited author, and cited journal, with pathfinder pruning.

**Key Results:** The first article was published in 1996, and annual publications and citations rose steadily, peaking in 2020/2021. A total of 42 countries/regions contributed. The US led with 507 publications (centrality 0.87, H-index 90), followed by England (117, centrality 0.18, H-index 39), China (95, centrality 0.2, H-index 23), Germany (66, centrality 0.16, H-index 28), and France (65, centrality 0.07, H-index 28). Among 449 institutions, the University of Florida ranked first (150 publications, centrality 0.43, H-index 53), followed by the University of Pennsylvania (86, centrality 0.37, H-index 49). The top funding agencies were predominantly US-based. The journal Molecular Therapy had the highest number of publications (78) and citations (6230), with an impact factor of 12.91 (Q1). The most productive author was Hauswirth WW (H-index 49, total citations 9851, 109 publications). The top 10 highly-cited articles focused on Leber congenital amaurosis (LCA) treatment, with the most cited being Maguire et al. (2008, 123 citations). Co-cited reference clusters included "retinal pigmented epithelium" (largest, 114 members, silhouette 0.904), "intravitreal vector delivery" (92 members, silhouette 0.893), and "retinal gene therapy" (79 members, silhouette 0.91). Keyword burst analysis showed "in vivo" (1999–2009), "recombinant AAV" (2001–2011), "transgene expression" (2001–2010), "ciliary neurotrophic factor" (2001–2011), "viral vector" (2003–2009), "canine model" (2006–2013), "LCA" (2009–2015), "macular degeneration" (2017–2019), and "efficacy" and "safety" (both 2019–2022). Of 80 clinical trials, 29 were completed; the first began in 2007, with a peak between 2018 and 2020. Diseases targeted included inherited retinal diseases (LCA, Leber hereditary optic neuropathy, retinitis pigmentosa, achromatopsia, retinoschisis, choroideremia, Stargardt disease) and acquired retinal diseases (neovascular AMD, dry AMD, diabetic retinopathy). LCA and wet AMD had the highest trial counts. The US conducted 54 trials, followed by the UK (20), France (11), and Germany (11).

**Clinical Implications:** This analysis demonstrates that AAV-based ocular gene therapy has transitioned from basic research to clinical application, with a growing focus on efficacy and safety. The expansion from monogenic inherited retinal diseases to acquired conditions like AMD highlights its broadening therapeutic potential. The leading role of US institutions and funding agencies underscores the importance of continued investment and international collaboration. The identification of key authors and institutions provides a roadmap for future partnerships. The emphasis on safety and efficacy in recent keywords suggests that ongoing and future trials will prioritize long-term outcomes and patient-centered endpoints, which is critical for regulatory approval and clinical adoption.