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Towards gene therapy for neurological damage associated with Friedreich's ataxia

The absence of frataxin, due to the mutation of the Frataxin gene, in certain neurons of sick mice leads to behavioural, physiological and cellular affections. For example, in sciatic nerves, axons in large sensory neurons degenerate with the affected myelin sheath and the presence of autophagous vacuoles (electron microscopy images). The gene therapy treatment of these sick mice, consisting in bringing a non-mutated version of the Frataxin gene using a viral vector, restores frataxin expression and corrects behavioural, physiological and cellular defects.

Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia.

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

Mol Ther Aug. 1, 2018

June 1, 2018

Friedreich's ataxia is a rare hereditary disease, characterized by neurodegenerative disease, heart disease and increased risk of diabetes, for which there is currently no treatment. Hélène Puccio’s, researcher at the IGBMC (CNRS/Inserm/University of Strasbourg) demonstrated the efficacy of a gene therapy on the neurodegenerative damage associated with Friedreich's Ataxia in mice. A double intravenous and intracerebral injection of a normal copy of the human frataxin gene via a viral vector rapidly corrected the neurological symptoms of the disease. Results published on June 1, 2018 in the journal Molecular Therapy.

Friedreich's ataxia, the most common hereditary ataxia, is an incurable progressive neurodegenerative disease. It is caused by a triplet nucleotide expansion in the frataxin gene, which leads to reduced levels of this protein essential to the activity of the cell's power plants, the mitochondria. In 2014, Hélène Puccio's team demonstrated the efficacy of gene therapy using a normal copy of the frataxin gene to prevent and rapidly reverse Friedreich's ataxia cardiomyopathy in a cardiac mouse model. However, little progress had been made on developing gene therapy approaches to treat the neurological symptoms, in particular the degeneration of sensory neurons of the dorsal root ganglia present along the spinal column as well as the cerebellum lesions.


In this study, Hélène Puccio's team presented a new mouse model deficient in frataxin specifically in certain neurons affected in Friedreich Ataxia, including the large sensory neurons, called proprioceptive neurons of the dorsal root ganglia, and the deep nuclei and the Purkinje cell of the cerebellum. The model develops a progressive mixed sensory and cerebellar ataxia, with a very specific defect in the sensori-motor reflexes, reproducing the primary symptoms observed in Friedreich Ataxia patients. Interestingly, despite being dysfunctional, the proprioceptive neurons can survive several weeks without frataxin, giving a large potential therapeutic window.


The researchers then injected a normal copy of the frataxin gene carried by a viral vector intravenously, targeting the dorsal root ganglia along the spine and intracerebrally to target the cerebellum of the affected mice. Following this double administration, the neurological symptoms at the behavioral, physiological and cellular levels were reversed in only a few days.


These results thus establish the proof of concept of the potential of gene therapy in the treatment of Friedreich's ataxia neuropathy and the establishement of a new neuronal model to study the neurophysiopathology of Friedreich Ataxia.

Imprimer Envoyer

Université de Strasbourg

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