Research Grant Award

Young Investigator Award

Marek Napierala, PhD

Institute of Biosciences and Technology-Center for Genome Research
DNA structure of GAA*TTC repeats as a target for Friedreich's ataxia therapy

Friedreich's ataxia (FRDA) is a severe genetic disorder affecting approximately 1 in 50,000 people in the Unites States. The most common FRDA symptoms include muscle weakness and loss of coordination, vision impairment, hearing loss, heart muscle abnormalities, scoliosis, and diabetes. First symptoms can usually be noticed between the ages of 5 and 15 and they progressively worsen. The underlying cause of FRDA is a mutation in the FRDA gene, specifically, in the fragment containing repeated runs of the GAA sequence (GuanineAdenineAdenine). Unaffected individuals have up to 30 tandemly repeated copies of the GAA sequence, while in the Friedreich's ataxia patients this sequence can be elongated up to 1700 copies. The consequence of this elongation is decreased production of the protein called frataxin.

Biochemical studies have shown that elongated GAA repeats adopt abnormal DNA structures. This length-dependent change in DNA structure is thought to be the primary molecular cause of the Friedreich's ataxia. The abnormal GAA structure blocks the expression of the FRDA gene leading to the frataxin deficiency. My goal is to analyze DNA structures that are formed by GAA repeats of different lengths and to determine how these structures affect the expression of the gene in living cells. I have designed a high-throughput system capable of screening thousands of chemical compounds in the search for new drugs. These drugs would target and destroy the abnormal GAA structures and therefore restore the production of the frataxin in the cells of FRDA patients.

These studies are intended to advance our knowledge about the molecular basis of the FRDA and apply this knowledge to the future therapeutic strategies.