Funding transnational collaborative research through joint transnational calls is one of the major objectives of E-Rare. This is the most important and effective joint activity to enhance the cooperation between European scientists working on rare diseases and thus reducing the fragmentation of research in this field. E-Rare launches calls on a yearly basis. The topic and eligibility criteria are specified every year and therefore may vary from one call to the other.

Gene Therapy for Cerebellar Ataxias: restoring cholesterol metabolism by targeting brain cholesterol 24 hydroxylase (CYP46A1)

Project Coordinator

INSERM - Molecular Imaging Research Center


Alexandra Durr INSERM 1127 Paris, France
Thorsten Schmidt University of Tuebingen Tuebingen, Germany
Maciej Figiel Polish Academy of Sciences - Institute of Bioorganic Chemistry Poznan, Poland
Luis Pereira de Almeida University of Coimbra Coimbra, Portugal

Impaired brain cholesterol metabolism plays a major role in neurodegenerative diseases like Parkinson (PD), Alzheimer (AD) and Huntington (HD). By transforming cholesterol into 24-HydroxyCholesterol (24-OHChol), CYP46A1 is a neuronal key enzyme that allows exporting cholesterol out of the brain therefore activating cholesterol turnover. We demonstrated that CYP46A1 is decreased in brains of AD and HD patients and mice. Moreover, 24-OHChol was reproductively decreased in the plasma of HD patients. Overexpressing CYP46A1 in affected brain regions using an Adeno-Associated Virus (AAV) vector corrects murine models of AD and HD. Importantly, it decreases aggregation of polyQ-mutated Huntingtin. Our preliminary data show that 1) both CYP46A1 and 24-OHChol are decreased in the affected cerebellum of a transgenic mouse model of polyQ cerebellar ataxia and CYP46A1 is decreased in the cerebellum of ScA3 patients; 2) AAV-CYP46A1 overexpression in a lentiviral-mouse model of SCA3 significantly decreases PolyQ aggregates and prevents neuronal death.
Our objectives are 1) to confirm the role of cholesterol metabolism dysfunction in polyQ Spinocerebellar Ataxias (SCAs) and 2) demonstrate the efficacy of an AAV-CYP46A1 gene therapy strategy in these disorders for which no efficient therapeutic option is available.
We propose to:
1) Characterize lipidomic modifications in plasma and brain tissue from SCA3 and SCA7 patients, as well as, SCA3 and SCA7 mouse models (partner 1, 2, 3, 4, associated partner; WP1)
2) Evaluate if AAV-CYP46A1 cerebellar injection can correct SCA3 Prp-MJD80 (Partner 3) and MJD Q69 (partner 1, associated partner) mouse models and SCA7 ATXN77 Q100 mouse model (partner 2; WP2).
3) Evaluate if CYP46A1 inhibition can induce a phenotype resembling SCA in normal mice and if it aggravates the phenotype of a SCA3 mild model (partner 1, 4; WP3).

E-Rare 2012 - Created by Toussaint Biger