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Current treatment options remain limited and largely focus on seizure management, which is often challenging to control, underscoring the critical need for new effective therapies. To identify potential novel candidate molecules for the treatment of CDD, we performed the first\n                  <jats:italic>in vivo<\/jats:italic>\n                  drug screening using a\n                  <jats:italic>cdkl5<\/jats:italic>\n                  mutant zebrafish model. Recapitulating key features of the human disorder,\n                  <jats:italic>cdkl5<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  larvae exhibit reduced locomotor behavior, providing a robust readout to assess therapeutic efficacy. By screening 170 compounds from MAPK Inhibitor and Histone Modification Libraries, both implicated in CDKL5 dysfunction, we identified 18 and 12 small molecules that partially or fully restored locomotor activity, respectively. Among these, fisetin, divalproex, resveratrol, and VX-702 were further evaluated for their capacity to rescue\n                  <jats:italic>cdkl5<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  craniofacial defects and altered gene expression. Fisetin demonstrated the most consistent phenotypic improvement, including partial restoration of craniofacial abnormalities and normalization of gene expression levels. Future research aimed at elucidating the molecular mechanisms underlying the observed rescue effects will be critical to understand their mode of action. Overall, our study demonstrates the utility of this rapid and scalable zebrafish-based screening approach for therapeutic discovery in CDD and identifies promising therapeutic molecules that warrant further validation in complementary preclinical systems.\n                <\/jats:p>","DOI":"10.64898\/2026.03.12.711124","type":"posted-content","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T16:55:12Z","timestamp":1773680112000},"source":"Crossref","is-referenced-by-count":0,"title":["Rescuing functional defects in a zebrafish model of CDKL5 deficiency disorder: Contribution to the identification of new therapeutic compounds"],"prefix":"10.64898","author":[{"given":"Tatiana","family":"Varela","sequence":"first","affiliation":[{"name":"Centre of Marine Sciences, University of Algarve, Faro, Portugal"},{"name":"Faculty of Medicine and Biomedical Sciences, University of Algarve, Faro, Portugal"}]},{"given":"D\u00e9bora","family":"Varela","sequence":"additional","affiliation":[{"name":"Centre of Marine Sciences, University of Algarve, Faro, Portugal"},{"name":"Faculty of Medicine and Biomedical Sciences, University of Algarve, Faro, Portugal"}]},{"given":"Jo\u00e3o","family":"Santos","sequence":"additional","affiliation":[{"name":"Centre of Marine Sciences, University of Algarve, Faro, Portugal"}]},{"given":"Ana","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Centre of Marine Sciences, University of Algarve, Faro, Portugal"}]},{"given":"Max","family":"Domingues","sequence":"additional","affiliation":[{"name":"Centre of Marine Sciences, University of Algarve, Faro, Portugal"}]},{"given":"Vanessa","family":"Pinto","sequence":"additional","affiliation":[{"name":"Centre of Marine Sciences, University of Algarve, Faro, Portugal"}]},{"given":"Nat\u00e9rcia","family":"Concei\u00e7\u00e3o","sequence":"additional","affiliation":[{"name":"Centre of Marine Sciences, University of Algarve, Faro, Portugal"},{"name":"Faculty of Medicine and Biomedical Sciences, University of Algarve, Faro, Portugal"},{"name":"Algarve Biomedical Center, University of Algarve, Faro, Portugal"}]},{"given":"M. Leonor","family":"Cancela","sequence":"additional","affiliation":[{"name":"Centre of Marine Sciences, University of Algarve, Faro, Portugal"},{"name":"Faculty of Medicine and Biomedical Sciences, University of Algarve, Faro, Portugal"},{"name":"Algarve Biomedical Center, University of Algarve, Faro, Portugal"}]}],"member":"54368","reference":[{"key":"2026031807150849000_2026.03.12.711124v1.1","doi-asserted-by":"crossref","first-page":"e341","DOI":"10.1016\/S2214-109X(24)00056-1","article-title":"The landscape for rare diseases in 2024","volume":"12","author":"The Lancet Global Health","year":"2024","journal-title":"Lancet Glob. 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