{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T16:54:09Z","timestamp":1781542449012,"version":"3.54.5"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Rett syndrome (RTT) is a severe neurodevelopmental disorder most commonly caused by loss-of-function mutations in the\n                      <jats:italic>MECP2<\/jats:italic>\n                      gene, including a substantial fraction of nonsense variants. Despite intense research efforts, no curative therapy is currently available for RTT, although several therapeutic strategies are under investigation. Among these, translational readthrough approaches, aimed at promoting ribosomal bypass of premature termination codons (PTCs) using small molecules, have attracted considerable attention in recent years. However, chemical readthrough agents raise concerns due to their limited specificity and the high sensitivity of MeCP2 to amino acid substitutions, underscoring the need for strategies capable of restoring full-length MeCP2 while preserving its amino acidic and functional integrity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Using cellular models expressing common RTT-associated nonsense variants of\n                      <jats:italic>MECP2<\/jats:italic>\n                      , we investigated the potential of anticodon-edited transfer RNAs (ACE-tRNAs) to selectively suppress\n                      <jats:italic>MECP2<\/jats:italic>\n                      nonsense mutations and restore full-length, functional MeCP2 protein.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We show that ACE-tRNAs promote efficient and dose-dependent readthrough, leading to the production of full-length MeCP2. Readthrough efficiency differed among nonsense mutations, with only specific variants benefitting from ACE-tRNA level optimization. Functional analyses revealed that ACE-tRNA\u2013rescued MeCP2 correctly localizes to heterochromatic foci and regains the ability to recruit the transcriptional corepressor TBL1, two hallmark features of MeCP2 activity. In contrast, scrambled control tRNAs failed to restore nuclear localization or protein\u2013protein interactions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Together, these findings demonstrate that ACE-tRNAs enable efficient and functionally relevant readthrough of\n                      <jats:italic>MECP2<\/jats:italic>\n                      nonsense mutations, highlighting mutation-specific requirements and supporting the feasibility of a precision readthrough strategy for RTT. Although further\n                      <jats:italic>in vivo<\/jats:italic>\n                      validation and delivery optimization is required, ACE-tRNA-based readthrough represents a promising and complementary strategy for the treatment of nonsense mutations associated with RTT.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1778877","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:26:02Z","timestamp":1780291562000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Anticodon-engineered tRNAs restore full-length MeCP2 expression and function in Rett syndrome nonsense mutations"],"prefix":"10.3389","volume":"17","author":[{"given":"Elena","family":"Fara","sequence":"first","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology Applied to Neurodevelopmental Disorders, Department of Medical Biotechnology and Translational Medicine, University of Milan","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Pezzini","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology Applied to Neurodevelopmental Disorders, Department of Medical Biotechnology and Translational Medicine, University of Milan","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ginevra","family":"Arpaia","sequence":"additional","affiliation":[{"name":"San Raffaele Rett Research Unit, Neuroscience Division, IRCCS San Raffaele Scientific Institute","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelisa","family":"Frasca","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Neurobiology, Department of Medical Biotechnology and Translational Medicine, University of Milan","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Porter","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Lueck","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester","place":["Rochester, NY, United States"]},{"name":"Department of Neurology, School of Medicine and Dentistry, University of Rochester","place":["Rochester, NY, United States"]},{"name":"Center for RNA Biology, School of Medicine and Dentistry, University of Rochester","place":["Rochester, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Landsberger","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology Applied to Neurodevelopmental Disorders, Department of Medical Biotechnology and Translational Medicine, University of Milan","place":["Milan, Italy"]},{"name":"San Raffaele Rett Research Unit, Neuroscience Division, IRCCS San Raffaele Scientific Institute","place":["Milan, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/s41572-024-00568-0","article-title":"Rett syndrome","volume":"10","author":"Gold","year":"2024","journal-title":"Nat Rev Dis Primers"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e000731","DOI":"10.1136\/bmjpo-2020-000731","article-title":"Multisystem comorbidities in classic Rett syndrome: a scoping review","volume":"4","author":"Fu","year":"2020","journal-title":"BMJ Paediatr 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