Among the recently distributed National Ataxia Foundation (NAF) research awards, Ricardo Mouro Pinto, Ph.D., from Massachusetts General Hospital Harvard Medical School, received a Young Investigator Award for his work on DNA repair genes that might contribute to the expansion of the GAA repeat mutation in Friedreich’s ataxia.
The stretches of repeats of three DNA bases in the frataxin gene are directly linked to disease severity — the more repeats present in the gene, the less frataxin is produced. Earlier studies have found that the repeats are not stable, but tend to expand, both when the gene is passed on from parent to child, and also within the lifetime of an individual. This is particularly true in tissues affected by the disease.
Mouro Pinto hypothesizes that this expansion with time might, in fact, be a driver of disease, triggering the onset and propelling progression as a patient gets older.
Scientists know that DNA repair genes — which, just as the name implies, help maintain the genome throughout the lifetime of a cell — are involved in the process by which the GAA repeats multiply, but exactly how this happens has still eluded researchers. Mouro Pinto believes this information is key for the development of new therapies for Friedreich’s ataxia. Directly targeting the mutation lies in understanding the molecular players and mechanisms of the GAA expansion in more detail.
Further support for this idea, according to Mouro Pinto, comes from a study of another disease caused by three-base-pair repeats — Huntington’s disease. The study looked at more than 4,000 Huntington’s patients, demonstrating that genes involved in pathways of DNA repair likely modifies age at the onset of disease, indicating that targeting these genes might be therapeutically meaningful.
Mouro Pinto will use a new gene-editing technique, the CRISPR-Cas9 system, to study DNA repair genes in mouse models of Friedreich’s ataxia, aiming to determine if these genes are involved in the expansion of the GAA repeats in peripheral tissue. The work also aims to explore whether these genes directly modify symptoms of Friedreich’s ataxia, paving the way for future therapeutic applications. The NAF award amounts to $35,000.