This application is aimed at understanding the molecular basis for the neurodegenerative disease Friedreich's ataxia (FRDA) and development of novel therapeutics. FRDA is one of the triplet-repeat diseases, where expansion of GAA.TTC repeats within the FXN gene, encoding the essential mitochondrial protein frataxin, leads to epigenetic transcriptional silencing. Loss of frataxin results in a spinocerebellar ataxia with secondary cardiomyopathy, which is the major cause of death in FRDA patients. At present there is no approved therapy for FRDA. Since the GAA.TTC repeats are in an intron, and do not affect the sequence of frataxin protein, gene activation would be of therapeutic value. We identified members of the 2-aminobenzamide class of HDAC inhibitors as potent activators of FXN transcription. These molecules cross the blood brain barrier in mice and canines, exhibit no acute or chronic toxicity, and increase FXN mRNA and frataxin protein levels in the brain and heart in the mouse FRDA model, as well as in circulating lymphocytes in drug-treated FRDA patients in a Phase Ib human clinical trial. While these data provide a proof of concept for this therapeutic approach, our current compounds suffer from pharmacological limitations that preclude their use in chronic treatment. Through a medicinal chemistry effort, we have identified new compounds that have solved these limitations, and one such molecule is being taken forward as a new clinical candidate. During the previous application period, we generated induced pluripotent stem cells (iPSCs) from FRDA patients and differentiated these cells along the neuronal lineage. We have used these cells to model FRDA to study FXN gene silencing and for drug screening. In the present application, we plan to (1) optimize methods for the differentiation of hiPSCs to sensory neurons, the major cell type affected in FRDA, and to use these cells to model the disease through global gene expression studies and markers of mitochondrial dysfunction. For these experiments, we will use helper-dependent adenovirus-mediated homologous recombination to generate isogenic cell lines have the GAA?TTC repeats """"""""corrected"""""""" to normal lengths. (2) Since cardiomyopathy is the major cause of death in FRDA, we will also model the disease in FRDA iPSC-derived cardiomyocytes. (3) We will use these two FRDA cell models to ask if improved HDAC inhibitors can reverse FRDA gene expression signatures and FRDA mitochondrial pathology. (4) Lastly, we will use neuronal cells and patient lymphocytes to identify gene expression biomarkers to be used in Phase II efficacy studies in FRDA patients. Our studies are at the forefront of development of a novel therapeutic for this currently untreatable and lethal disease.

Public Health Relevance

This application is aimed at understanding the molecular basis and pathophysiology of the inherited neurodegenerative disease Friedreich's ataxia (FRDA) and development of histone deacetylase (HDAC) inhibitors as therapeutics for this disease. We found that FRDA is an epigenetic gene silencing disease, and our efforts focus on using patient induced pluripotent stem cell-derived cell types to both model the disease and to screen our therapeutic compounds.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gwinn, Katrina
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Scripps Research Institute
La Jolla
United States
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Gottesfeld, Joel M; Carey, Michael F (2018) Introduction to the Thematic Minireview Series: Chromatin and transcription. J Biol Chem 293:13775-13777
Soragni, Elisabetta; Gottesfeld, Joel M (2016) Translating HDAC inhibitors in Friedreich's ataxia. Expert Opin Orphan Drugs 4:961-970
Soragni, Elisabetta; Chou, C James; Rusche, James R et al. (2015) Mechanism of Action of 2-Aminobenzamide HDAC Inhibitors in Reversing Gene Silencing in Friedreich's Ataxia. Front Neurol 6:44
Shan, Bing; Xu, Chunping; Zhang, Yaoyang et al. (2014) Quantitative proteomic analysis identifies targets and pathways of a 2-aminobenzamide HDAC inhibitor in Friedreich's ataxia patient iPSC-derived neural stem cells. J Proteome Res 13:4558-66
Soragni, Elisabetta; Miao, Wenyan; Iudicello, Marco et al. (2014) Epigenetic therapy for Friedreich ataxia. Ann Neurol 76:489-508
Gottesfeld, Joel M; Rusche, James R; Pandolfo, Massimo (2013) Increasing frataxin gene expression with histone deacetylase inhibitors as a therapeutic approach for Friedreich's ataxia. J Neurochem 126 Suppl 1:147-54
Polak, Urszula; Hirsch, Calley; Ku, Sherman et al. (2012) Selecting and isolating colonies of human induced pluripotent stem cells reprogrammed from adult fibroblasts. J Vis Exp :
Du, Jintang; Campau, Erica; Soragni, Elisabetta et al. (2012) Role of mismatch repair enzymes in GAA·TTC triplet-repeat expansion in Friedreich ataxia induced pluripotent stem cells. J Biol Chem 287:29861-72
Soragni, Elisabetta; Xu, Chunping; Plasterer, Heather L et al. (2012) Rationale for the development of 2-aminobenzamide histone deacetylase inhibitors as therapeutics for Friedreich ataxia. J Child Neurol 27:1164-73
Jia, Haiqun; Pallos, Judit; Jacques, Vincent et al. (2012) Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's disease. Neurobiol Dis 46:351-61

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