{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T08:49:45Z","timestamp":1791535785700,"version":"4.3.4"},"reference-count":27,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"13","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,3,28]]},"abstract":"<jats:p>Retinal gene therapy using dual adeno-associated viral (AAV) intein vectors can be applied to genetic forms of blindness caused by mutations in genes with coding sequences that exceed single AAV cargo capacity, such as Stargardt disease (STGD1), the most common inherited macular dystrophy. In view of clinical translation of dual AAV intein vectors, here we set to evaluate both the efficiency and safety of their subretinal administration in relevant large animal models. Accordingly, we have developed the first pig model of STGD1, which we found to accumulate lipofuscin similarly to patients. This accumulation is significantly reduced upon subretinal administration of dual AAV intein vectors whose safety and pharmacodynamics we then tested in nonhuman primates, which showed modest and reversible inflammation as well as high levels of photoreceptor transduction. This bodes well for further clinical translation of dual AAV intein vectors in patients with STGD1 as well as for other blinding diseases that require the delivery of large genes.<\/jats:p>","DOI":"10.1126\/sciadv.adt9354","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T18:45:32Z","timestamp":1743014732000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":21,"title":["Retinal gene therapy for Stargardt disease with dual AAV intein vectors is both safe and effective in large animal models"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-0749","authenticated-orcid":true,"given":"Rita","family":"Ferla","sequence":"first","affiliation":[{"name":"AAVantgarde Bio srl, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Pugni","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8425-1266","authenticated-orcid":true,"given":"Mariangela","family":"Lupo","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7970-4980","authenticated-orcid":true,"given":"Paola","family":"Tiberi","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8332-5430","authenticated-orcid":true,"given":"Federica","family":"Fioretto","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy."},{"name":"Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0387-8724","authenticated-orcid":true,"given":"Andrea","family":"Perota","sequence":"additional","affiliation":[{"name":"Avantea, Laboratory of Reproductive Technologies, Cremona, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9904-8488","authenticated-orcid":true,"given":"Roberto","family":"Duchi","sequence":"additional","affiliation":[{"name":"Avantea, Laboratory of Reproductive Technologies, Cremona, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Lagutina","sequence":"additional","affiliation":[{"name":"Avantea, Laboratory of Reproductive Technologies, Cremona, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Gesualdo","sequence":"additional","affiliation":[{"name":"Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Settimio","family":"Rossi","sequence":"additional","affiliation":[{"name":"Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9330-979X","authenticated-orcid":true,"given":"Domenico","family":"Ventrella","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell\u2019Emilia, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7827-5034","authenticated-orcid":true,"given":"Alberto","family":"Elmi","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell\u2019Emilia, Italy."},{"name":"Department of Veterinary Sciences, University of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"McClinton","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research, University of Leeds, Leeds, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8373-9545","authenticated-orcid":true,"given":"Carmel","family":"Toomes","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research, University of Leeds, Leeds, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongzhou","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Molecular Biology, Department of Ophthalmology &amp; Visual Sciences, Centre for Macular Research University of British Columbia, Vancouver, B.C., Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4479-1831","authenticated-orcid":true,"given":"Robert S.","family":"Molday","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; Molecular Biology, Department of Ophthalmology &amp; Visual Sciences, Centre for Macular Research University of British Columbia, Vancouver, B.C., Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-942X","authenticated-orcid":true,"given":"Enrico M.","family":"Surace","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Federico II University, Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Simonelli","sequence":"additional","affiliation":[{"name":"Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6702-5868","authenticated-orcid":true,"given":"Maria L.","family":"Bacci","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell\u2019Emilia, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9529-6136","authenticated-orcid":true,"given":"Cesare","family":"Galli","sequence":"additional","affiliation":[{"name":"Avantea, Laboratory of Reproductive Technologies, Cremona, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0665-0197","authenticated-orcid":true,"given":"Muhammad A.","family":"Memon","sequence":"additional","affiliation":[{"name":"AAVantgarde Bio srl, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8484-6032","authenticated-orcid":true,"given":"Naveed","family":"Shams","sequence":"additional","affiliation":[{"name":"AAVantgarde Bio srl, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0832-2472","authenticated-orcid":true,"given":"Alberto","family":"Auricchio","sequence":"additional","affiliation":[{"name":"AAVantgarde Bio srl, Milan, Italy."},{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy."},{"name":"Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3134-2973","authenticated-orcid":true,"given":"Ivana","family":"Trapani","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy."},{"name":"Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2021.101036"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.013"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1802519115"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2023.126"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav4523"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1006\/exer.2002.1181"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv386"},{"key":"e_1_3_2_9_2","first-page":"243","article-title":"A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells","volume":"22","author":"Di Lauro S.","year":"2016","unstructured":"S. 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