Research Grant Award

Elisabeth Soragni, PhD

The Scripps Research Institute
Development of Histone Deacetylase Inhibitors as Therapeutics for Friedreich's Ataxia

Friedreich's ataxia (FRDA) is caused by transcriptional repression of the FXN gene encoding the essential protein frataxin. This defect is caused by the expansion of a simple repetitive DNA sequence in the gene that causes the gene to shut down. In consequence of this expansion frataxin protein is not expressed at sufficient levels, hence the neurological symptoms and the accumulation of iron in the heart of FRDA patients. Currently there is no effective treatment for FRDA. Antioxidants and iron chelators have been tested in preclinical studies and clinical trials and have proven to achieve limited success in alleviating symptoms. We believe that a more effective therapeutic strategy would be to restore normal levels of frataxin protein. To this purpose we developed a library of molecules that can activate FXN transcription and increase frataxin protein in cell culture. We intend to further develop our library to achieve maximal effectiveness and wish to understand the mode of action of these compounds at a molecular level. We demonstrated that these molecules reach the brain when administered to normal mice and exhibit no acute toxicity. We will use mouse models for the disease to establish whether our molecules are able to increase the levels of frataxin in the mouse brain and relieve the symptoms of the disease in mice.