Neuronal Gene Therapy for Friedreich Ataxia

Authors
F Piguet, C de Montigny, N Vaucamps, L Reutenauer, A Eisenmann, H Puccio

Lab
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France

Journal
Molecular Therapy

Abstract
Friedreich ataxia (FA) is a rare mitochondrial disease characterized by sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy, and diabetes, for which there is no treatment. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin-positive cells that recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, although fully dysfunctional, proprioceptive neurons can survive for many weeks without frataxin. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue of the sensory neuropathy associated with frataxin deficiency, thus establishing the pre-clinical proof of concept for the potential of gene therapy in treating FA neuropathy.

BIOSEB Instruments Used:
Aron Test or Four Plates Test (LE830),Infrared Actimeter (LE8815),Rotarod (BX-ROD)