{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T16:30:59Z","timestamp":1779121859326,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T00:00:00Z","timestamp":1622160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["Allelechoker 311682  InSight 813223"],"award-info":[{"award-number":["Allelechoker 311682  InSight 813223"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gene-expression programs modulated by transcription factors (TFs) mediate key developmental events. Here, we show that the synthetic transcriptional repressor (TR; ZF6-DB), designed to treat Rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-adRP), does not perturb murine retinal development, while maintaining its ability to block Rho expression transcriptionally. To express ZF6-DB into the developing retina, we pursued two approaches, (i) the retinal delivery (somatic expression) of ZF6-DB by Adeno-associated virus (AAV) vector (AAV-ZF6-DB) gene transfer during retinogenesis and (ii) the generation of a transgenic mouse (germ-line transmission, TR-ZF6-DB). Somatic and transgenic expression of ZF6-DB during retinogenesis does not affect retinal function of wild-type mice. The P347S mouse model of RHO-adRP, subretinally injected with AAV-ZF6-DB, or crossed with TR-ZF6-DB or shows retinal morphological and functional recovery. We propose the use of developmental transitions as an effective mode to challenge the safety of retinal gene therapies operating at genome, transcriptional, and transcript levels.<\/jats:p>","DOI":"10.3390\/ijms22115767","type":"journal-article","created":{"date-parts":[[2021,5,28]],"date-time":"2021-05-28T11:33:20Z","timestamp":1622201600000},"page":"5767","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Challenging Safety and Efficacy of Retinal Gene Therapies by Retinogenesis"],"prefix":"10.3390","volume":"22","author":[{"given":"Elena","family":"Marrocco","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, 80078 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Maritato","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvatore","family":"Botta","sequence":"additional","affiliation":[{"name":"Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1151-7913","authenticated-orcid":false,"given":"Marianna","family":"Esposito","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, 80078 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-942X","authenticated-orcid":false,"given":"Enrico Maria","family":"Surace","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1056\/NEJMra1706910","article-title":"Gene Therapy","volume":"381","author":"High","year":"2019","journal-title":"N. 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