Development of an improved GAA repeat expansion mutation-based mouse model of Friedreich ataxia for therapeutic testing

Principal researcher : Dr. Mark Pook Biosciences Division, Brunel University, Uxbridge, UK.

Lay summary: Friedreich ataxia (FRDA) is a lethal inherited neurological disorder for which there is currently no effective therapy. The disease is caused by both parents passing on a DNA mutation, known as a “repeat expansion”. This leads to reduced levels of an important protein, frataxin, within cells. Although potential treatments of some later symptoms are now being investigated, it may be more effective to treat the early stages of disease, producing an increase in frataxin protein. Within this application we firstly aim to obtain some indication of the effectiveness of potential FRDA therapies from studying cells that are cultured in the laboratory. However, ultimately this is an artificial situation that does not necessarily relate to how the therapy will work on a whole complex organism. Therefore, the use of a mouse model of FRDA to study potential therapies is considered essential. We have recently established a good FRDA mouse model that is useful for therapeutic studies. However, the symptoms of disease in this model are rather mild, so we would now like to develop an improved model that has more severe symptoms, thereby increasing the effectiveness of preclinical therapeutic studies. In particular, we plan to test our FRDA mouse model with several different compounds that have good potential for frataxin-increasing FRDA therapy. The results that we obtain will be invaluable when considering which drugs may be suitable for future clinical trials.