Friedreich's ataxia (FRDA), is the most common autosomal recessive movement disorder, and cripples about 6000 Americans, and tens of thousands worldwide, and there is no approved therapy. FRDA is progressive, striking in the teen years, and its phenotype includes primary neurodegeneration and demyelination of sensory dorsal root ganglion (DRG) neurons. New drugs cost $1B to develop, and it is sometimes difficult to motivate pharma to invest in diseases that affect thousands rather than millions of people. We have undertaken a translational screen of 1600 internationally-approved drugs, i.e. drugs that have undergone phase I, II, and III trials already, to identify which of these can be most rapidly repurposed for treatment of FRDA patients. We microarrayed the DRG neurons of the best mouse model of FRDA available (YG8), and observed defects in several molecules reduced by thioredoxin reductase, including GSH. We used this deficiency to screen 1600 currently-approved drugs for their ability to rescue FRDA patient cells from death, and identified 40. Of those drugs, some increase frataxin expression, whereas others are likely to support iron-sulfur cluster biogenesis.
Our first Aim i ncludes the determination of mechanism of action of the 40 drugs (Aim 1), with respect to frataxin expression, Fe/S cluster synthesis, and PGC-1alpha induction.
In Aim 2, the drugs will be tested in tissue-relevant Schwann cell and DRG neurons for rescue of Fe/S cluster, heme defects and death. Also in Aim 2 the ability of normal frataxin and pathogenic point mutations known to cause FRDA to rescue Fe/S cluster, heme and cell viability will be determined.
In Aim 3 we will test the activity of the 9 most diamide-protective drugs for their ability to rescue frataxin expression, iron-sulfur cluster defects, and auranofin sensitivity in the context of DRG explants. Furthermore, in vivo dosing of the 3 most potent drugs will occur, and effects on DRG frataxin expression, iron-sulfur defects, and auranofin sensitivity will be measured. Lastly for the most effective two drugs, 3-month studies of rescue from behavioral and iron-sulfur biochemical defects will be carried out.
In Aim 4, a specific hypothesis for the relationship of age- and tissue-specific somatic expansions of (GAA)n will be tested, by quantitative PCR of repeats and frataxin and ironsulfur cluster proteins. At the end of this translational research project, we expect to have prioritized the mechanism of action and potency of several anti-Friedreich's therapeutic drugs that have already passed through phase I, II and III trials, in FRDA patient cells and the best available animal model of the disease, as a preliminary to clinical testing in humans, and to have to have confirmed or rejected a novel hypothesis for the selective vulnerability of DRG neurons in the disease.
Friedreich's ataxia (FRDA) is a crippling neurodegenerative disease initiating in teen years. Based on investigation of the disease we identified a biochemical difference in FRDA patient cells, and have screened 1600 drugs already approved for use in humans, and have identified 40 which protect the cells from death. Our goals are to determine the mechanism of action of the drugs and efficacy in cell and animal models in preparation for clinical testing in humans.
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