{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T02:22:04Z","timestamp":1791685324147,"version":"4.3.4"},"reference-count":73,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T00:00:00Z","timestamp":1717372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lejeune Fondation","award":["1855"],"award-info":[{"award-number":["1855"]}]},{"name":"Lejeune Fondation","award":["ANR-10-IAIHU-06"],"award-info":[{"award-number":["ANR-10-IAIHU-06"]}]},{"name":"Lejeune Fondation","award":["ANR-11-INBS-0011"],"award-info":[{"award-number":["ANR-11-INBS-0011"]}]},{"name":"program \u201cInvestissements d\u2019avenir\u201d","award":["1855"],"award-info":[{"award-number":["1855"]}]},{"name":"program \u201cInvestissements d\u2019avenir\u201d","award":["ANR-10-IAIHU-06"],"award-info":[{"award-number":["ANR-10-IAIHU-06"]}]},{"name":"program \u201cInvestissements d\u2019avenir\u201d","award":["ANR-11-INBS-0011"],"award-info":[{"award-number":["ANR-11-INBS-0011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Rett syndrome (RTT) is a rare neurodevelopmental disorder caused by mutation in the X-linked gene methyl-CpG-binding protein 2 (Mecp2), a ubiquitously expressed transcriptional regulator. RTT results in mental retardation and developmental regression that affects approximately 1 in 10,000 females. Currently, there is no curative treatment for RTT. Thus, it is crucial to develop new therapeutic approaches for children suffering from RTT. Several studies suggested that RTT is linked with defects in cholesterol homeostasis, but for the first time, therapeutic evaluation is carried out by modulating this pathway. Moreover, AAV-based CYP46A1 overexpression, the enzyme involved in cholesterol pathway, has been demonstrated to be efficient in several neurodegenerative diseases. Based on these data, we strongly believe that CYP46A1 could be a relevant therapeutic target for RTT. Herein, we evaluated the effects of intravenous AAVPHP.eB-hCYP46A1-HA delivery in male and female Mecp2-deficient mice. The applied AAVPHP.eB-hCYP46A1 transduced essential neurons of the central nervous system (CNS). CYP46A1 overexpression alleviates behavioral alterations in both male and female Mecp2 knockout mice and extends the lifespan in Mecp2-deficient males. Several parameters related to cholesterol pathway are improved and correction of mitochondrial activity is demonstrated in treated mice, which highlighted the clear therapeutic benefit of CYP46A1 through the neuroprotection effect. IV delivery of AAVPHP.eB-CYP46A1 is perfectly well tolerated with no inflammation observed in the CNS of the treated mice. Altogether, our results strongly suggest that CYP46A1 is a relevant target and overexpression could alleviate the phenotype of Rett patients.<\/jats:p>","DOI":"10.3390\/pharmaceutics16060756","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T10:08:38Z","timestamp":1717409318000},"page":"756","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Modulation of Brain Cholesterol Metabolism through CYP46A1 Overexpression for Rett Syndrome"],"prefix":"10.3390","volume":"16","author":[{"given":"Emilie","family":"Audouard","sequence":"first","affiliation":[{"name":"TIDU GENOV, Institut du Cerveau, ICM, F-75013 Paris, France"},{"name":"Institut du Cerveau, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5711-0600","authenticated-orcid":false,"given":"Nicolas","family":"Khefif","sequence":"additional","affiliation":[{"name":"Institut du Cerveau, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9atrix","family":"Gillet-Legrand","sequence":"additional","affiliation":[{"name":"Institut du Cerveau, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Nobilleau","sequence":"additional","affiliation":[{"name":"Institut du Cerveau, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ouafa","family":"Bouazizi","sequence":"additional","affiliation":[{"name":"Institut du Cerveau, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1454-0713","authenticated-orcid":false,"given":"Serena","family":"Stanga","sequence":"additional","affiliation":[{"name":"Neuroscience Institute Cavalieri Ottolenghi, 10043 Orbassano, Italy"},{"name":"Department of Neuroscience Rita Levi Montalcini, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00ebtan","family":"Despres","sequence":"additional","affiliation":[{"name":"Saint Antoine Research Center, INSERM UMR 938, D\u00e9partement de M\u00e9tabolomique Clinique, H\u00f4pital Saint Antoine, AP-HP Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1396-7523","authenticated-orcid":false,"given":"Sandro","family":"Alves","sequence":"additional","affiliation":[{"name":"Institut du Cerveau, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonin","family":"Lamazi\u00e8re","sequence":"additional","affiliation":[{"name":"Saint Antoine Research Center, INSERM UMR 938, D\u00e9partement de M\u00e9tabolomique Clinique, H\u00f4pital Saint Antoine, AP-HP Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Cartier","sequence":"additional","affiliation":[{"name":"Institut du Cerveau, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7861-7199","authenticated-orcid":false,"given":"Fran\u00e7oise","family":"Piguet","sequence":"additional","affiliation":[{"name":"TIDU GENOV, Institut du Cerveau, ICM, F-75013 Paris, France"},{"name":"Institut du Cerveau, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universit\u00e9, F-75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett Syndrome Is Caused by Mutations in X-Linked MECP2, Encoding Methyl-CpG-Binding Protein 2","volume":"23","author":"Amir","year":"1999","journal-title":"Nat. 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