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Apr 24, 2014
 |  BC Innovations  |  Targets & Mechanisms

Reversing (heart) failure in Friedreich's ataxia

Heart failure accounts for over half the deaths in patients with Friedreich's ataxia, but no therapies exist to treat this neurodegenerative disease or its associated cardiomyopathy. Now, a team of French researchers has shown that i.v. frataxin gene therapy could prevent or even reverse heart failure in a mouse model of Friedreich's ataxia.1

AAVLife S.A.S., a new company founded by several team members, has licensed the findings and will test dosing and safety of direct cardiac injection of the gene therapy in healthy pigs.

Friedreich's ataxia (FRDA) is caused by inherited loss-of-function mutations in frataxin (FXN; FRDA), which encodes a mitochondrial protein involved in the assembly of iron-sulfur clusters that are essential to mitochondrial energy production.

FXN deficiency leads to degeneration of the spinal cord, resulting in progressive loss of motor function in the limbs, scoliosis, impaired vision and hearing, and speech problems. FXN deficiency also causes iron overload in cardiac mitochondria and impairs bioenergetics, thus contributing to heart failure.

There are no disease-modifying therapies to treat FRDA. Instead, disease management can include physical therapy to aid motor control, surgery to correct scoliosis and angiotensin-converting enzyme (ACE) inhibitors or other drugs that treat heart failure.

Thus, a team led by Hélène Puccio set out to test whether an adeno-associated virus serotype 10 (AAV10) vector encoding human FXNcould treat cardiomyopathy in conditional Fxn knockout models of FRDA.

Puccio is director of Institut National de la Santé et de la Recherche Médicale (INSERM) research and head of the Department of Translational Medicine and Neurogenetics at the Institute of Genetics and Molecular and Cellular Biology.

In 2001, a group led by Puccio developed a conditional Fxn knockout mouse model-Fxn -/- mice are nonviable because of embryonic lethality-that recapitulated key features of human FRDA, including cardiomyopathy and large sensory neuron dysfunction.2

In 2012, a team led by Ronald Crystal, chair of genetic medicine and a professor of internal medicine at Weill Cornell Medical College, showed that AAV10 exhibited significant tropism for the heart and liver-and to a lesser degree the dorsal root ganglia (DRG)-of nonhuman primates.3

The two groups connected after Crystal began collaborating on a different AAV-related project with Patrick Aubourg, who was familiar with Puccio's...

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