Friedreich’s Ataxia: Gene Therapy on the Right Track


Friedreich’s ataxia, the most common hereditary ataxia, is a progressive neurodegenerative disease that remains incurable to date. But for the first time, an Inserm team has been able to restore motor functions in mice with neurodegeneration mimicking that seen in humans.

An Inserm team is counting on gene therapy to slow the neuronal degeneration affecting sufferers of Friedreich’s ataxia. This disease is expressed by disorders of balance and coordination of voluntary movements (ataxia), and also by heart disease, diabetes and, often, osteoarticular disorders (scoliosis, high-arched feet). It is a genetic disease caused by a mutation affecting the frataxin gene. The mutation leads to the loss of function of this protein which is essential to the activity of the cell's power plants, the mitochondria.

Friedreich’s ataxia is a rare condition affecting roughly 1 in 50,000 people, i.e. approximately 1,300 patients in France. With onset generally towards the age of 9 to 14 years, its development and symptoms vary from one patient to another. However, the inability to walk generally manifests 10 to 20 years after the first symptoms. No treatment exists at present.

In 2014, the team of Hélène Puccio, Inserm research director at the Institute of Genetics and of Molecular and Cell Biology* (Strasbourg), had developed gene therapy using a viral vector carrying a functional copy of the frataxin gene. The objective was to combat the cardiac abnormalities associated with the disease in a mouse model. This approach paid off, making it possible not only to prevent symptoms but also to reverse them. However, in the absence of a reliable animal model for the study of neuronal degeneration, it was not possible to test the therapy on this component of the disease.

Four years later, not only are the researchers presenting a new animal model reproducing the sensory and cerebellar ataxia of Friedreich’s disease, but by using this new model they are also showing the efficacy of a gene therapy intended to cure the neurological symptoms.

A therapeutic window in which to act

"Neuronal dysfunction begins in the proprioceptive neurons of the dorsal-root ganglia present along the spinal column, but it is also present in the cerebellum. The proprioceptive neurons are responsible for deep sensitivity. They enable you to position yourself in space, to know where the different parts of your body are with your eyes closed. Their loss forces you to constantly readjust your movements. When the cerebellum is affected, notably the dentate nucleus, the problems are accentuated with difficulty regulating voluntary movements," explains Puccio. Her team was able to reproduce some of these events in mice by deactivating the frataxin gene in the proprioceptive neurons as well as in the Purkinje cells and the gray nuclei present in the cerebellum.

The researchers then observed a loss of function of these cells, without it leading to their immediate death: this suggests the existence of a therapeutic window during which it would still be possible to restore the activity of these neurons. It remains to be verified whether this also exists in humans and, if so, to define its duration. "In mice, the neurons do not die straightaway. The therapeutic window is around ten weeks, which is very long," comments Puccio. "But in patients with Friedreich’s ataxia, it is difficult to know whether the proprioceptive neurons are still present at the time of diagnosis. Only the data obtained from post-mortem autopsies, years after the start of the disease, show that the proprioceptive neurons have disappeared," she explains.

Regression of the symptoms

Effects of Friedreich’s ataxia gene therapy in a mouse model of the disease © Hélène Puccio

The researchers have used their new model to test the therapeutic efficacy of gene therapy: a viral vector containing a functional copy of the frataxin gene was injected into the animals both by the intravenous and intracerebellar routes, to ensure that the various target cells no longer expressing frataxin are reached. A few days later, they observed a restoration of cellular activity and a regression of the symptoms with a return to normal behavior.

The next stage would be to test in a clinical setting, but it's still too early for this phase. "First, we need to develop a viral vector that can be used in the clinic, test the best route for its administration, and verify its distribution in the body. We also need to decide on the patients to enroll. Must we treat at a very early stage when the symptoms are modest or wait with the risk that the neurons have already disappeared?" wonders the researcher.

In the meantime, the development of this new animal model gives the team a better understanding of the pathophysiology of the disease and neuron deregulation, and we might even find new treatments on top of everything.


*unit 964 Inserm/CNRS/Université de Strasbourg, Institute of Genetics and of Molecular and Cell Biology (IGBMC), Fundamental and pathophysiological mechanisms implicated in recessive ataxia team, Illkirch

Source : F Piguet et coll. Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia. Mol Ther, édition en ligne du 28 mai 201