{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:13:44Z","timestamp":1786122824787,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: We aimed to provide an updated synthesis of the efficacy and ocular safety of subretinal adeno-associated viral (AAV) RPGR gene therapy for retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (RPGR-XLRP) and to assess the certainty of the available evidence. Methods: We performed a PROSPERO-registered (CRD420251163589), PRISMA 2020 systematic review and meta-analysis using database and trial-registry searches. The primary microperimetry synthesis was restricted to mesopic Macular Integrity Assessment (MAIA) 68-loci acquisitions; continuous-outcome syntheses were conducted at the cohort level, using observed paired-eye contrasts when available; dose levels were interpreted within clinical programs; and above-maximum-tolerated-dose and peripheral-injection cohorts were reported separately. Random-effects analyses used DerSimonian\u2013Laird models with Hartung\u2013Knapp\u2013Sidik\u2013Jonkman small-sample correction. Risk of bias and certainty were assessed with design-matched tools and Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: The quantitative synthesis included four trials reported in five publications (128 participants; AAV8, AAV5, and AAV2tYF platforms). Mesopic retinal sensitivity numerically favored treatment, but the pooled differences were not statistically significant at six months (mean difference [MD] +1.11 dB; 95% confidence interval [CI], \u22120.88 to +3.09) or twelve months (MD +0.97 dB; 95% CI, \u22123.99 to +5.94). Best-corrected visual acuity showed no statistically significant pooled difference (MD +0.94 letters; 95% CI, \u22124.97 to +6.85). The six-month \u226510-letter low-luminance responder estimate favored treatment, but was nonsignificant and attenuated by twelve months; no primary pooled efficacy outcome reached significance under small-sample-adjusted inference. Certainty was very low for functional outcomes and low for safety outcomes. Uncontrolled treated-eye proportions were 80.8% for intraocular inflammation, 17.0% for ocular serious adverse events, and 4.3% for central-injection retinal detachment. Conclusions: Current evidence does not establish a clinically actionable functional benefit, although a modest true effect cannot be excluded. Clinically relevant ocular safety signals were observed, but the estimates were uncontrolled and program dependent. Adequately powered randomized trials with standardized functional endpoints, optimized subretinal delivery strategies, and careful within-program dose selection are needed.<\/jats:p>","DOI":"10.3390\/jcm15166144","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:44:53Z","timestamp":1786103093000},"page":"6144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional Outcomes and Ocular Safety of Subretinal AAV-RPGR Gene Therapy for RPGR-Associated X-Linked Retinitis Pigmentosa: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2355-2217","authenticated-orcid":false,"given":"Carlos Roberto","family":"Montes-de-Oca-Saucedo","sequence":"first","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Antonio","family":"Garza-Cruz","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Brice\u00f1o-Villardaga","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid Vanessa","family":"Infante-Lee","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Chavarr\u00eda-Rojas","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie Carled","family":"Bermejo-Valero","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Soto-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of Medicine, Universidad Autonoma de Nuevo Leon, Monterrey 64460, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5495-7153","authenticated-orcid":false,"given":"Neeran","family":"Narainswami","sequence":"additional","affiliation":[{"name":"Division of Ophthalmology, Red Cross War Memorial Children\u2019s Hospital and Groote Schuur Hospital, University of Cape Town, Cape Town 7700, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1167\/iovs.61.14.36","article-title":"Spectrum of disease severity in patients with X-linked retinitis pigmentosa due to RPGR mutations","volume":"61","author":"Karali","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/IAE.0000000000003920","article-title":"A systematic literature review of disease progression reported in RPGR-associated X-linked retinitis pigmentosa","volume":"44","author":"Lam","year":"2024","journal-title":"Retina"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1167\/iovs.06-0971","article-title":"Disease course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations","volume":"48","author":"Sandberg","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/aos.14662","article-title":"Natural history and clinical biomarkers of progression in X-linked retinitis pigmentosa: A systematic review","volume":"99","author":"Zada","year":"2021","journal-title":"Acta Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100375","DOI":"10.1016\/j.xops.2023.100375","article-title":"Visual acuity by decade in 139 males with RPGR-associated retinitis pigmentosa","volume":"4","author":"Chan","year":"2024","journal-title":"Ophthalmol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/s41433-024-03546-8","article-title":"The burden of X-linked retinitis pigmentosa (XLRP) on patient experience and patient-reported outcomes (PROs): Findings from the EXPLORE XLRP-2 study","volume":"39","author":"Parmeggiani","year":"2025","journal-title":"Eye"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/s41591-020-0763-1","article-title":"Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR","volume":"26","author":"Xue","year":"2020","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1001\/jamaophthalmol.2022.6254","article-title":"Changes in retinal sensitivity associated with cotoretigene toliparvovec in X-linked retinitis pigmentosa with RPGR gene variations","volume":"141","author":"Liu","year":"2023","journal-title":"JAMA Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.ajo.2024.05.034","article-title":"Phase 1\/2 AAV5-hRKp.RPGR (botaretigene sparoparvovec) gene therapy: Safety and efficacy in RPGR-associated X-linked retinitis pigmentosa","volume":"267","author":"Michaelides","year":"2024","journal-title":"Am. J. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ajo.2024.11.021","article-title":"Subretinal gene therapy drug AGTC-501 for XLRP phase 1\/2 multicenter study (HORIZON): 24-month safety and efficacy results","volume":"271","author":"Yang","year":"2025","journal-title":"Am. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1002\/cpt.3230","article-title":"Clinical pharmacology perspective on development of adeno-associated virus vector-based retina gene therapy","volume":"115","author":"Ford","year":"2024","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s40291-024-00722-0","article-title":"Gene therapies in clinical development to treat retinal disorders","volume":"28","author":"McClements","year":"2024","journal-title":"Mol. Diagn. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.1167\/iovs.17-22077","article-title":"High symmetry of visual acuity and visual fields in RPGR-linked retinitis pigmentosa","volume":"58","author":"Bellingrath","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1111\/aos.14816","article-title":"Clinical applications of microperimetry in RPGR-related retinitis pigmentosa: A review","volume":"99","author":"Buckley","year":"2021","journal-title":"Acta Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1167\/tvst.12.6.4","article-title":"Microperimetry as an outcome measure in RPGR-associated retinitis pigmentosa clinical trials","volume":"12","author":"Taylor","year":"2023","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1167\/tvst.10.2.28","article-title":"Low luminance visual acuity and low luminance deficit in choroideremia and RPGR-associated retinitis pigmentosa","volume":"10","author":"Wood","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.ajo.2021.07.018","article-title":"Characterization of retinal function using microperimetry-derived metrics in both adults and children with RPGR-associated retinopathy","volume":"234","author":"Anikina","year":"2022","journal-title":"Am. J. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1167\/iovs.18-24931","article-title":"Progression in X-linked retinitis pigmentosa due to ORF15-RPGR mutations: Assessment of localized vision changes over 2 years","volume":"59","author":"Cideciyan","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100595","DOI":"10.1016\/j.xops.2024.100595","article-title":"XOLARIS: A 24-month, prospective, natural history study of 201 participants with retinitis pigmentosa GTPase regulator-associated X-linked retinitis pigmentosa","volume":"5","author":"MacLaren","year":"2025","journal-title":"Ophthalmol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jolly, J.K., Bridge, H., and MacLaren, R.E. (2019). Outcome measures used in ocular gene therapy trials: A scoping review of current practice. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01076"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1167\/tvst.15.3.5","article-title":"Efficacy and safety of gene therapy for RPGR gene-associated X-linked retinitis pigmentosa: A systematic review and meta-analysis","volume":"15","author":"Yang","year":"2026","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/s41586-020-2649-2","article-title":"Array programming with NumPy","volume":"585","author":"Harris","year":"2020","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: Fundamental algorithms for scientific computing in Python","volume":"17","author":"Virtanen","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials","volume":"7","author":"DerSimonian","year":"1986","journal-title":"Control. Clin. Trials"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"IntHout, J., Ioannidis, J.P.A., and Borm, G.F. (2014). The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-25"},{"key":"ref_27","unstructured":"Higgins, J.P.T., Thomas, J., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2024). Cochrane Handbook for Systematic Reviews of Interventions. Version 6.5, Cochrane. Available online: https:\/\/www.cochrane.org\/authors\/handbooks-and-manuals\/handbook."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.ophtha.2024.02.023","article-title":"XIRIUS Study Group. Assessment of visual function with cotoretigene toliparvovec in X-linked retinitis pigmentosa in the randomized XIRIUS phase 2\/3 study","volume":"131","author":"Lam","year":"2024","journal-title":"Ophthalmology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: An emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"Guyatt","year":"2008","journal-title":"BMJ"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.jclinepi.2018.01.012","article-title":"GRADE guidelines: 18. How ROBINS-I and other tools to assess risk of bias in nonrandomized studies should be used to rate the certainty of a body of evidence","volume":"111","author":"Schunemann","year":"2019","journal-title":"J. Clin. Epidemiol."},{"key":"ref_33","unstructured":"Research with Human Subjects (2026, July 17). Phase 3 Randomized, Controlled Study of AAV5-hRKp.RPGR for the Treatment of X-Linked Retinitis Pigmentosa Associated with Variants in the RPGR Gene. NL-OMON52296; MGT-RPGR-021; NCT04671433. Available online: https:\/\/onderzoekmetmensen.nl\/en\/trial\/52296."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Josan, A.S., Taylor, L.J., Raji, S., Cehajic-Kapetanovic, J., and MacLaren, R.E. (2026). Microperimetry as an outcome measure improves patient eligibility and efficacy detection in RPGR gene therapy trials. Am. J. Ophthalmol., Epub ahead of print.","DOI":"10.1016\/j.ajo.2026.06.002"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1111\/ceo.13753","article-title":"Test-retest repeatability of microperimetry in patients with retinitis pigmentosa caused by mutations in RPGR","volume":"48","author":"Buckley","year":"2020","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/aos.16780","article-title":"Test-retest variability of mesopic microperimetry-associated parameters in patients with retinitis pigmentosa: RE-PEAT Study Report No. 2","volume":"103","author":"Karuntu","year":"2025","journal-title":"Acta Ophthalmol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Cedr\u00fan-S\u00e1nchez, J.E., Povedano-Montero, F.J., Chamorro, E., S\u00e1nchez-Ramos, C., and Puell, M.C. (2025). Mesopic and low-contrast visual acuity deficits in retinitis pigmentosa: Clinical markers for early functional impairment. J. Clin. Med., 14.","DOI":"10.3390\/jcm14165659"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.ajo.2025.11.002","article-title":"Central retinal sensitivity decline in RPGR-related retinal phenotypes","volume":"282","author":"Josan","year":"2026","journal-title":"Am. J. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.ophtha.2014.11.005","article-title":"Rates of decline in fdOCT-defined regions of the visual field in patients with RPGR-mediated X-linked retinitis pigmentosa","volume":"122","author":"Birch","year":"2015","journal-title":"Ophthalmology"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Rover, C., Knapp, G., and Friede, T. (2015). Hartung-Knapp-Sidik-Jonkman approach and its modification for random-effects meta-analysis with few studies. BMC Med. Res. Methodol., 15.","DOI":"10.1186\/s12874-015-0091-1"},{"key":"ref_41","unstructured":"Montes-de-Oca-Saucedo, C.R., Garza-Cruz, J.A., Infante-Lee, I.V., Chavarr\u00eda-Rojas, R., Bermejo-Valero, N.C., and Soto-Dom\u00ednguez, A. (2026, January 3\u20137). Subretinal AAV-RPGR gene therapy for X-linked retinitis pigmentosa: A meta-analysis of human patients. Poster presentation no. 5784. Proceedings of the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, Denver, CO, USA."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/16\/6144\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:54:30Z","timestamp":1786103670000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/16\/6144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":41,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["jcm15166144"],"URL":"https:\/\/doi.org\/10.3390\/jcm15166144","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,7]]}}}