Research Grant Award

Joseph P Sarsero, PhD (B.Sc. Honrs)

Murdoch Children's Research Institute
Generation of improved mouse models of Friedreich ataxia for pharmacological testing

Friedreich ataxia is an inherited disorder of the nervous system and heart. The genetic defect that causes Friedreich ataxia results in reduced levels of an essential protein termed frataxin in all cells of the body. Using information and resources generated as part of the Human Genome Project we have developed new techniques to study human gene expression in cellular and animal systems. Our aim is to identify and develop new pharmacological approaches for the restoration of Friedreich ataxia gene expression and the therapy of Friedreich ataxia.

We have identified a number of agents that are able to increase the expression of the Friedreich ataxia gene and are in the process of screening many currently approved drugs for their effects on the Friedreich ataxia gene.

Prior to evaluating new therapies in patients it is important that they be tested in appropriate biological models of the disease. Animal models of human disease that are generated by the 'knockout' of specific genes often manifest the main traits or symptoms of the corresponding human disorder. Thus they have proved invaluable in the understanding of the role of various genes and the development of many therapeutic strategies. However, such models rarely recapitulate the precise molecular cause that underlies human disease, thus limiting the development of therapeutic options that may depend on overcoming the specific effects of each disease-causing mutation.

Accurate 'humanized' mouse models of disease are designed to contain an entire human gene of interest and surrounding regulatory regions, and also harbor the specific disease-causing mutation as found in patients. Such mice do not only manifest the main traits or symptoms of a disorder, but also provide the correct underlying molecular cause of the disease as found in patients.

We have made significant headway in the generation of humanized mouse models of FA containing the entire human Friedreich ataxia gene with a disease-causing alteration. In this project we propose to improve our current Friedreich ataxia mouse models so that they more accurately reflect appropriate disease symptoms. We shall then test newly identified pharmacological agents on these improved mouse models. Any compounds which are able to alleviate the symptoms of Friedreich ataxia in the mice have a great chance of acting in a positive manner in persons with Friedreich ataxia.