Regulation of frataxin expression – implications for Friedreich's ataxia therapy

Friedreich’s ataxia (FRDA), a severe progressive neurodegenerative disorder, is caused by an increasing number of specific DNA sequences, termed GAA repeats, that are present in the Friedreich’s ataxia gene (FXN). This error in DNA causes a block in the flow of information from DNA to RNA and ultimately leads to a deficiency of the final FXN product, a protein called frataxin. One of the major types of therapeutic approaches for FRDA currently being developed tries to counteract this frataxin deficiency. In order for the therapy to be successful, we need to determine the minimum amount of frataxin increase that will be beneficial for patients, as well as the maximum possible increase of frataxin that will not cause any negative consequences. This is called a therapeutic window and is an essential parameter for therapy development for FRDA. Also, to better understand the dosing of potential drugs that could increase frataxin levels, the results of the proposed work will determine the ways that frataxin production, maintenance, and removal are controlled. In summary, this work contributes to the development of critical therapeutic guidelines for the treatment of frataxin deficiency in Friedreich’s ataxia.