{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:34:44Z","timestamp":1791232484952,"version":"4.1.0"},"reference-count":56,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"792","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,4,2]]},"abstract":"<jats:p>\n                    Conventional methods of gene transfer lead to inconsistent transgene expression within cells. This variability can be problematic, particularly in conditions like Rett syndrome (RTT), a neurological disorder caused by mutations in the\n                    <jats:italic>MECP2<\/jats:italic>\n                    (methyl-CpG binding protein 2) gene, because overexpression of\n                    <jats:italic>MECP2<\/jats:italic>\n                    can also cause adverse effects. To address these challenges, we devised a gene regulation system called Expression Attenuation via Construct Tuning (EXACT), which uses a self-contained, microRNA-based feed-forward loop that not only ensures more consistent transgene expression but also protects against excessive expression. Through cell-based screening assays, we demonstrated the ability of the EXACT circuit to modulate the expression of full-length human MeCP2. Compared with a conventional construct, an EXACT-\n                    <jats:italic>MECP2<\/jats:italic>\n                    construct exhibited a narrower range of cellular protein abundance. Furthermore, the degree of regulation by the EXACT circuit increased with higher transgene doses in vitro and in wild-type mice and mice modeling RTT. On the basis of cellular and in vivo testing, we identified an optimal configuration for the adeno-associated virus serotype 9 (AAV9) construct for self-regulated\n                    <jats:italic>MECP2<\/jats:italic>\n                    gene therapy, designated NGN-401. Delivery of NGN-401 to neonatal male\n                    <jats:italic>\n                      Mecp2\n                      <jats:sup>\u2212\/y<\/jats:sup>\n                    <\/jats:italic>\n                    hemizygous mice via intracerebroventricular injection resulted in prolonged survival and amelioration of RTT-like phenotypes compared with vehicle-treated animals. NGN-401 was also well tolerated by female\n                    <jats:italic>\n                      Mecp2\n                      <jats:sup>+\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice and healthy juvenile nonhuman primates, in contrast with a conventional construct, which caused toxicity. The results from these studies underpin a first-in-human pediatric trial of NGN-401 in RTT (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/ClinicalTrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    , NCT05898620).\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adq3614","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T16:32:02Z","timestamp":1743611522000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":25,"title":["Self-regulating gene therapy ameliorates phenotypes and overcomes gene dosage sensitivity in a mouse model of Rett syndrome"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4093-5703","authenticated-orcid":true,"given":"Paul D.","family":"Ross","sequence":"first","affiliation":[{"name":"Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-8953","authenticated-orcid":true,"given":"Kamal K. 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