NAF Ataxia Research Studies Currently Underway

Irene De Biase, MD, PhD

Board of Regents of the University of Oklahoma Health Sciences Center
Somatic instability in the pathogenesis and treatment of Friedreich ataxia

Summary: Friedreich ataxia is the most common inherited ataxia. It is caused when patients inherit large expansions of a GM triplet-repeat mutation from either parent. Whereas everyone who inherits these mutations develops disease, patients show a remarkable degree of variability in clinical manifestations. Even though the size of the GM triplet-repeat mutation generally determines the severity of disease, frequently individuals with the same size of repeat show very different clinical severities. Moreover, individuals who inherit mutations are usually asymptomatic until their teenage years, at which time the disease initiates, and then progresses relentlessly. Another confounding feature is that some regions of the nervous system degenerate early in the disease process compared with other regions, and some regions remain normal throughout. The causes of the individual variability despite inheriting similar mutations, the progressive nature of disease, and the selective damage to specific regions of the nervous system remain unknown. We believe that the reason stems from the behavior of the GM triplet-repeat mutation in specific tissues and its alteration during the aging of patients. We have found promising preliminary evidence to support our hypothesis and would like to comprehensively address this issue by analyzing the behavior of this mutation in various tissues derived from autopsies of ten individuals who died of Friedreich I ataxia. Our ultimate goal is to develop strategies to alter the behavior of this repeat sequence, slowing or preventing further expansion, in patient cells as a potential mechanism to slow the progression of disease. We propose to test various chemotherapeutic drugs in patient cells cultured in the lab in order to test their effect on altering the behavior of the GM triplet-repeat I mutation. We believe that our studies will help to better understand why the disease is progressive, and perhaps yield clues to the development of strategies to slow the progression of disease.