Research Highlight December 01, 2013

Efforts to treat Friedreich's ataxia gain momentum through research partnerships

 

Friedreich's ataxia (FA) is a debilitating, life-shortening, degenerative neuromuscular disorder characterized by loss of coordination in the arms and legs; energy deprivation; impairment of vision, hearing and speech; aggressive scoliosis; diabetes; and a serious heart condition. There is currently no treatment or cure.

Through a partnership between the Friedreich's Ataxia Research Alliance (FARA) — a foundation whose mission is to marshal and focus the resources and relationships needed to cure this disease — and many allies, we are ensuring that the mouse models for Friedreich's ataxia are well-standardized, genetically stable and available to the scientific community.

Friedreich's Ataxia Research Alliance (FARA)

FARA, which raises funds for research, promotes public awareness and aligns scientists, patients, clinicians, government agencies and pharmaceutical companies dedicated to curing FA, enlisted researchers who created and developed models to generously share these mice with JAX to establish colonies for comparative characterization and distribution. Researchers Massismo Pandolpho (University of Brussels), Mark Pook (Brunel University, London), Helene Puccio (University of Strausberg), and Joseph Sarseso (Murdoch Children's Institute) are among those participating in this joint effort.

Ron Bartek, President and Founder of FARA, approached The Jackson Laboratory in 2008 for help in standardizing the preclinical mouse models for Friedreich's ataxia. JAX is currently comparing the different FA models with a focus on identifying clinically relevant phenotypes that may be useful in evaluating drugs for efficacy.

Therapeutic strategies for Friedrich's ataxia

Friedreich's ataxia is caused by deficiency of the protein frataxin (FXN). An intronic expansion of GAA triplets in the frataxin gene causes gene silencing and results in reduced FXN protein levels (Figure 1). Silencing of the frataxin FXN gene by expanded GAA repeats is due to condensation of the gene into a form of chromatin, called heterochromatin, that blocks copying the gene into messenger RNA. This results in a loss of frataxin protein compared to healthy individuals. Heterochromatin is controlled by a class of enzymes call histone deacetylases or HDACs that remove the acetyl groups from the histones. HDAC inhibitors reverse gene silencing by directly increasing acetylation which leads to chromatin decondensation and more frataxin protein.

HDAC inhibtors are a promising strategy for treating Friedreich's ataxia. Repligen Corp. is working on a class of HDAC inhibitors that specifically target the FXN gene.

Benefits for patients of other genetic diseases

Although there are only a few thousand U.S. patients, Friedreich's ataxia affects thousands elsewhere in the Americas, Europe, Australia, New Zealand and the Middle East. In addition the disease shares commonalities in its underlying mechanisms, genetic mutations and therapeutic approaches with other diseases that result in less ATP production and increased oxidative stress, such as Parkinson's, Huntington's and other neuromuscular diseases, Alzheimer's, Fragile X Syndrome, and many more. These similar disease mechanisms point the way to broad collaboration and partnership for further research across disease groups.

References

Gatchel JR, Zoghbi HY. 2005. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 6(10):743-55.