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

Fontenay aux Roses


Maciej Figiel Polish Academy of sciences Poznan, Poland
Thorsten Schmidt Medical Genetics University of Tübingen Tübingen Tübingen, Germany
Luis Pereira de Almeida University of Coimbra Coimbra, Portugal
Alexandra Durr Université Pierre et Marie Curie Paris Paris, France

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 24OHChol 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) AAVCYP46A1 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 AAVCYP46A1 gene therapy strategy in these disorders for which no efficient therapeutic option is available.

E-Rare 2012 - Created by Toussaint Biger