{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:44:01Z","timestamp":1787028241205,"version":"build-2736575974"},"reference-count":119,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Inherited retinal diseases (IRDs) represent a genetically heterogeneous group of disorders caused by mutations in over 280 genes with more than 3100 identified variants. While gene-specific replacement therapies have achieved landmark success with voretigene neparvovec (Luxturna) for biallelic RPE65-associated retinal dystrophy, developing individual therapies for each genetic subtype remains impractical. This review examines gene-agnostic therapeutic approaches utilizing neuroprotection and immunomodulation that target common pathophysiological mechanisms shared across multiple IRD genotypes. Methods: We reviewed the literature on neuroprotective and immunomodulatory gene therapy strategies for IRDs, focusing on neurotrophic factors and complement system modulation. Results: Neuroprotective approaches delivering neurotrophic factors\u2014including pigment epithelium-derived factor (PEDF), ciliary neurotrophic factor (CNTF), rod-derived cone viability factor (RdCVF), brain-derived neurotrophic factor (BDNF), fibroblast growth factors (FGFs), glial cell line-derived neurotrophic factor (GDNF), and proinsulin\u2014have demonstrated photoreceptor preservation across multiple preclinical IRD models regardless of the underlying genetic mutation. The recent FDA approval of CNTF cell-based gene therapy (Encelto) for macular telangiectasia type 2 validates this therapeutic paradigm. Complement system inhibition represents another gene-agnostic strategy, with intravitreal complement inhibitors approved for geographic atrophy secondary to age-related macular degeneration and gene therapy approaches targeting C3, C5, or delivering soluble complement regulators under investigation for IRDs. Combination strategies simultaneously addressing multiple pathogenic pathways may offer synergistic benefits. Conclusions: Gene-agnostic approaches targeting neuroprotection and immunomodulation offer a therapeutic paradigm capable of benefiting patients across the spectrum of IRD genotypes, potentially transforming treatment for conditions where mutation-specific therapies remain unavailable.<\/jats:p>","DOI":"10.3390\/genes17040392","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:11:59Z","timestamp":1774872719000},"page":"392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Gene-Agnostic Therapeutic Strategies for Inherited Retinal Diseases: Neuroprotection and Immunomodulation"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1225-154X","authenticated-orcid":false,"given":"Lucas W.","family":"Rowe","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8004-4983","authenticated-orcid":false,"given":"S. Patricia","family":"Becerra","sequence":"additional","affiliation":[{"name":"Laboratory of Retinal Cell and Molecular Biology, Section of Protein Structure and Function, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"MacLaren","sequence":"additional","affiliation":[{"name":"Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK"},{"name":"Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Avery","sequence":"additional","affiliation":[{"name":"California Retina Consultants, Santa Barbara, CA 93103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7756-5091","authenticated-orcid":false,"given":"Charles C.","family":"Wykoff","sequence":"additional","affiliation":[{"name":"Retina Consultants of Texas, Bellaire, TX 77401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen C.","family":"Ho","sequence":"additional","affiliation":[{"name":"Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl D.","family":"Regillo","sequence":"additional","affiliation":[{"name":"Wills Eye Hospital, Mid Atlantic Retina, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Eliott","sequence":"additional","affiliation":[{"name":"Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Osborne","sequence":"additional","affiliation":[{"name":"Ikarovec Ltd., Norwich NR4 7GJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie M.","family":"Binley","sequence":"additional","affiliation":[{"name":"Ikarovec Ltd., Norwich NR4 7GJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5557-6777","authenticated-orcid":false,"given":"Thomas A.","family":"Ciulla","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Glick Eye Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA"},{"name":"Ikarovec Ltd., Norwich NR4 7GJ, UK"},{"name":"Retina Service, Midwest Eye Institute, Indianapolis, IN 46290, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101244","DOI":"10.1016\/j.preteyeres.2024.101244","article-title":"Phenotyping and Genotyping Inherited Retinal Diseases: Molecular Genetics, Clinical and Imaging Features, and Therapeutics of Macular Dystrophies, Cone and Cone-Rod Dystrophies, Rod-Cone Dystrophies, Leber Congenital Amaurosis, and Cone Dysfunction Syndromes","volume":"100","author":"Georgiou","year":"2024","journal-title":"Prog. 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