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To date, no cure is available for treating this disease. In 90% of the cases, RTT is caused by a mutation in methyl\u2010CpG\u2010binding protein 2 (MECP2), a transcription factor involved in the repression and activation of transcription. MECP2 is known to regulate several target genes and is involved in different physiological functions. Mouse models exhibit a broad range of phenotypes in recapitulating human RTT symptoms; however, understanding the disease mechanisms remains incomplete, and many potential RTT treatments developed in mouse models have not shown translational effectiveness in human trials. Recent data hint that the zebrafish model emulates similar disrupted neurological functions following mutation of the <jats:italic>mecp2<\/jats:italic> gene. This suggests that zebrafish can be used to understand the onset and progression of RTT pathophysiology and develop a possible cure. In this review, we elaborate on the molecular basis of RTT pathophysiology in humans and model organisms, including rodents and zebrafish, focusing on the zebrafish model to understand the molecular pathophysiology and the development of therapeutic strategies for RTT. Finally, we propose a rational treatment strategy, including antisense oligonucleotides, small interfering RNA technology and induced pluripotent stem cell\u2010derived cell therapy.<\/jats:p>","DOI":"10.1002\/jgm.3677","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T11:30:12Z","timestamp":1708515012000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Zebrafish in understanding molecular pathophysiology, disease modeling, and developing effective treatments for Rett syndrome"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3328-6239","authenticated-orcid":false,"given":"Subrata","family":"Pramanik","sequence":"first","affiliation":[{"name":"Jyoti and Bhupat Mehta School of Health Sciences and Technology Indian Institute of Technology Guwahati  Guwahati Assam India"},{"name":"Centre for Nanotechnology Indian Institute of Technology Guwahati  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