Identification of histone deacetylase inhibitors for reversing gene expression profiles in Huntington's disease striatal cells

• Applicant: Dr. Christine Jespersen
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2009 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 137565379

Huntington’s disease (HD) is the most prevalent autosomal inherited neurodegenerative disorder, affecting approximately 5-10:100,000 individuals worldwide. The disease is characterized by progressive motor dysfunction, cognitive deterioration and psychiatric disturbances. Usually the onset of the disease occurs between the ages of 30 and 50 and generally within 15 to 20 years after the first appearance of symptoms, the disease is invariably fatal. Numerous studies have pointed to histone deacetylase (HDAC) inhibitors as potential therapeutics for HD. However, the HDAC inhibitors that have been tested to date are highly cytotoxic agents and have low specificities for different HDAC enzymes. In the course of studies on the neurodegenerative disease Friedreich’s ataxia, the laboratory of Prof. Gottesfeld identified a novel class of HDAC inhibitors (pimelic diphenylamides) that reverse heterochromatin-mediated silencing of the frataxin gene in this disease. Previous studies indicate that at least one member of these molecules shows clinical efficacy in a mouse model for HD. A list of compounds with distinct specificities for different HDACs will be tested as potential therapeutics for HD. These substances will be tested in different cellular models, at first in well established mouse striatal cell lines provided by Dr. MacDonald. As a second model system, newly generated induced pluripotent stem cell lines (iPS) originally derived from a patient with HD will be used. The cell lines are commercially available at the Harvard Stem Cell Institute. A human neuronal HD model will be established by differentiating HD iPS cells into striatal neuronal cells in vitro.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Joel M. Gottesfeld, Ph.D.