Early in 2008, the Friedreich’s Ataxia Research Alliance (FARA) engaged The Jackson Laboratory to discuss opportunities to have Friedrich's Ataxia (FA) mouse models brought into JAX and made available to the research community. The Jackson Laboratory manages a repository for mouse models of human disease, with an extensive emphasis on neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease and spinal muscular atrophy (SMA). The Friedrich's Ataxia models are now a unique and important component of the neurodegenerative models at The Jackson Laboratory. "Each model tells us more about the biology of neurodegeneration, and it’s especially exciting to see models like the FA mice moving into the realm of preclinical trials," said Cathy Lutz, Ph.D., associate director of The Jackson Laboratory repository.
Friedrich's Ataxia is an autosomal recessive neurodegenerative disorder that is predominantly caused by a homozygous GAA repeat expansion mutation within intron 1 of the frataxin (FXN) gene. FA affects about one in 50,000 U.S. citizens. Onset is usually between the ages of 5 and 15. Symptoms include muscle weakness and loss of coordination (ataxia) in the arms and legs, vision and hearing loss, slurred speech, diabetes mellitus (in about 10% of FA patients) and hypertrophic cardiomyopathy, a serious complication and the most common cause of death in FA patients. As is the case for many neurodegenerative disorders, there is no cure or effective treatment for Friedrich's Ataxia.
FARA is a national, non-profit organization dedicated to curing Friedrich's Ataxia. Its grants and activities provide support for basic and translational research, pharmaceutical/biotech drug development, clinical trials, and scientific conferences. FARA is also a catalyst for worldwide exchanges of information that advance Friedrich's Ataxia research. FARA strongly believes in the power of partnership and collaboration with government agencies, corporations and advocacy groups. It helped fund the construction of new FA models and is very excited to facilitate increased access to its FA mouse models. Says Ron Bartek, FARA President, "FARA recognizes The Jackson Laboratory as a world-renowned non-profit facility with world-class personnel. We feel privileged to have established this important partnership with them, especially now as we are identifying more and more drug candidates for potential clinical evaluation. The Friedreich's Ataxia mouse models that The Jackson Laboratory houses, distributes, and improve for our scientists will be invaluable in helping determine which of the drugs show the most promise of moving into clinical trials and toward our objective of treatments and a cure."
This partnership between JAX and FARA will provide many benefits to the Friedrich's Ataxia research community, including the following:
Due to advancements in Friedrich's Ataxia drug discovery and development, several unique mouse models constructed by FA researchers (Helene Puccio, Ph.D., Massimo Pandolfo M.D., and Joseph Sarsero, Ph.D.) are in high demand and are now distributed by The Jackson Laboratory. Of particular interest is B6.Cg-Fxntm1Mkn Tg(FXN)YG8Pook/J (008398), constructed by Mark Pook, Ph.D., of Brunel University. It contains a 370kb YAC insert that includes the entire human FXN gene with GAA triplet repeat sequences. Founder line YG8, carrying two tandem copies of the human FXN gene with two GAA trinucleotide repeat sequences of 82 and 190 repeats, was established.
This transgenic line was then mated to one carrying the mouse Fxn-null allele generated by Michel Koenig, M.D., Ph.D., and Helene Puccio, Ph.D., resulting in a strain that displays an age-dependent tissue expansion of the GAA repeat (Al-Mahdawi et al. 2004, 2008). Says Dr. Pook: "As these Friedreich Ataxia mice have been generated by using the human GAA repeat expansion mutation to produce an FA-like phenotype, they are very useful to many researchers throughout the world who are either trying to unravel early events in the FA disease mechanism or investigating any type of potential FA therapy."
Al-Mahdawi S, Pinto RM, Ruddle P, Carroll C, Webster Z, Pook M. 2004. GAA repeat instability in Friedreich ataxia YAC transgenic mice. Genomics 84:301-10.
Al-Mahdawi S, Pinto RM, Ismail O, Varshney D, Lymperi S, Sandi C, Trabzuni D, Pook M. 2008. The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues. Hum Mol Genet 17:735-46.