Friedreich’s Ataxia Accelerator
Friedreich’s ataxia (FA) is a debilitating neurodegenerative disorder that afflicts approximately 1 in 50,000 people in the United States. This rare disease occurs when cells don’t produce enough of a mitochondrial protein called frataxin.
Often diagnosed during childhood, patients with FA typically show loss of coordination in their arms and legs (ataxia), lose the ability to walk, and suffer from a host of other conditions, such as scoliosis, heart failure, diabetes, and vision and hearing loss. This recessive disease is caused by an expansion of trinucleotide GAA repeats in DNA sequence within the frataxin gene (FXN). While the genetic basis of FA has been known for more than 20 years, there are still no approved therapies for patients, and basic questions about the mechanisms of disease remain unanswered.
At the Broad, the Friedreich’s Ataxia Accelerator brings to bear the Institute’s deep expertise in genomics to address these questions and discover new and effective FA treatments. Led by Institute Member Vamsi Mootha, co-director of the Metabolism Program, this highly collaborative effort leverages multiple Institute platforms and capabilities to illuminate the biological underpinnings of FA, with the goals of producing more therapeutic possibilities.
Building off exciting research supported by the CureFA Foundation, Mootha’s team made the surprising discovery that low oxygen (hypoxia) conditions improved outcomes of cells, worms, and mice that lacked FXN. Specifically, worms lacking FXN have never been generated prior to now—but in low-oxygen environments, these worms not only survive but also complete their entire reproductive life cycle. Excitingly, mouse models of FA that were exposed to chronic low oxygen also showed greatly reduced symptoms of ataxia. These studies in model systems open up a host of new experimental avenues with therapeutic potential.
Now, with funding from the Friedreich’s Ataxia Research Alliance (FARA), the Friedreich’s Ataxia Accelerator team is simultaneously pursuing fundamental and applied research in the following three therapeutic areas:
- Oxygen-inspired therapy. Since FA mouse models housed in low oxygen showed dramatic improvement in neurological symptoms, the Friedreich’s Ataxia Accelerator aims to determine which FA phenotypes can be prevented or reversed by hypoxia, and identify a practical regimen of hypoxia or a hypoxia-in-a-pill mimetic that could eventually be translated into human studies.
- Small molecule therapy. The Friedreich’s Ataxia Accelerator will also launch phenotypic screens, leveraging new cellular and worm models that have been generated thanks to the Mootha team’s insights into hypoxia and FA. The first portion of this two-pronged approach will involve drug screens performed in collaboration with the Broad’s Center for the Development of Therapeutics and Drug Repurposing Hub, which hosts a collection of more than 6,000 small molecules that are either approved or have undergone safety testing in humans. In parallel, the team will perform host microbe screens in close collaboration with the Gary Ruvkun laboratory at Harvard Medical School to identify microbe-derived factors that alleviate disease.
- Genome editing. The Broad Institute also is leveraging its long-standing genomics prowess to propel discovery in genetically precise therapies for FA. Core Institute Member David Liu and his team will explore whether their cutting-edge genomic editing technologies can interrupt the disease-causing mutations that occur within FXN. If successful, the approach could point the way to a precision medicine solution for FA.