Gene Therapy Fully Reverses Friedreich’s Ataxia Changes in Mouse Model, Study Shows

A gene therapy approach to deliver frataxin, the protein that’s deficient in Friedreich’s ataxia (FA) patients, was able to reverse disease-related changes in a new mouse model of the disease, a French study reports.

The study, “Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia,” appeared in the journal Molecular Therapy.

Sensory ataxia, the lack of movement coordination due to loss of sensory input about body position, is an early event in FA. Neurological symptoms in this disease mainly result from degeneration of sensory neurons and their nerve fibers in the spinal cord and the cerebellum.

Possible therapies for FA may come from diverse approaches, including gene therapy. The authors previously showed that a gene therapy strategy using harmless viruses to deliver frataxin could prevent and reverse cardiomyopathy, or heart muscle disease, in a mouse model of FA. However, the question of whether sensory peripheral nerve damage (neuropathy) could be reversed remained unanswered.

In this study, scientists developed a new FA mouse model, which they considered better suited for testing gene therapy strategies for the primary sensory ataxia associated with this disorder.

This new model more specifically targets proprioceptive neurons, which are responsible for transmitting information about body position, movement, and balance. The mice were also engineered to enable conditional deletion of frataxin in cells expressing parvalbumin, a calcium-binding protein involved in various physiological processes, such as muscle contraction, and found in muscle, brain, and other types of tissue.

Researchers found that the new model mimics the sensory ataxia and nerve damage associated with FA, although with a more rapid and severe course. Mice exhibited a progressive loss of coordination and gait alterations.

They also observed that alterations in the central nervous system, including the cerebellum, occurred after disease onset in the periphery. Neurons lacking frataxin, although dysfunctional, could survive for many weeks, the scientists reported.

They then delivered viral vectors (carriers) containing frataxin into the vein, which completely prevented the start of peripheral sensory nerve damage. Combined intravenous and brain delivery of these vectors after the onset of behavioral impairment reversed behavioral, physiological, and cellular changes within a week.

“Our results strongly demonstrate that frataxin-deficient proprioceptive neurons with severe phenotype survive for several weeks and can be rapidly and completely rescued by gene therapy in the mouse model,” the researchers wrote. “Thus, this study establishes the pre-clinical proof of concept for the potential of gene therapy in treating FA sensory neuropathy.”