Modulation of Brain Cholesterol Metabolism through CYP46A1 Overexpression for Rett Syndrome
Open accessAbstract
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.
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Restoring Cyp46a1 expression in Mecp2 KO mice significantly ameliorated disease manifestations.
“reporting that restoring Cyp46a1 expression in Mecp2 KO mice significantly ameliorated disease manifestations (Audouard et al., 2024), providing independent evidence that improving cholesterol homeostasis leads to behavioral benefits.”
From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Audouard et al., 2024
Results §3.2 reports significantly reduced hindlimb clasping and improved survival in treated Mecp2 KO male mice. But the treatment overexpressed human CYP46A1 rather than restoring deficient Cyp46a1 expression: the Discussion states that endogenous mouse Cyp46A1 expression was not altered in Mecp2 mice. (LLM, conf=0.88)
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- Authors
- Audouard, E., Khefif, N., Gillet-Legrand, B., Nobilleau, F., Bouazizi, O., Stanga, S., Despres, G., Alves, S., Lamazière, A., Cartier, N., & Piguet, F.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Neuroscience Institute Cavalieri Ottolenghi (IT)
- Saint Antoine Research Center, INSERM UMR 938, Département de Métabolomique Clinique, Hôpital Saint Antoine, AP-HP Sorbonne Université, F-75013 Paris, France
- Inserm (FR)
- Corresponding author
- Piguet, Françoise
- ORCID
- Venue
- Pharmaceutics
- Publisher
- MDPI AG
- Published
- 2024-06-03
- Volume
- 16
- Issue
- 6
- Pages
- 756
- ISSN
- 1999-4923 (ISSN-L)
- PMC
- PMC11207948
- OpenAlex
- W4399287334
- Cited by
- 7
- References
- 75
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 2
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Pharmaceutics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Lejeune Fondation (1855, ANR-10-IAIHU-06, ANR-11-INBS-0011)
- program “Investissements d’avenir” (1855, ANR-10-IAIHU-06, ANR-11-INBS-0011)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Rett syndrome, CYP46A1, cholesterol metabolism, cholesterol homeostasis, MeCP2 deficiency, AAV gene therapy, neuroprotection, mitochondrial function, lifespan extension, Mecp2 knockout mice, neurodevelopmental disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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