This application is aimed at the development of a novel stem cell-based therapeutic approach for the inherited neurodegenerative disease Friedreich’s ataxia (FRDA). FRDA is caused by a genetic mutation within a gene called frataxin (FXN). Frataxin protein is involved in energy production in the mitochondria of human cells. This mutation, a GAA•TTC triplet-repeat expansion, causes gene silencing, resulting in an insufficiency of frataxin protein in affected individuals. Current therapeutic approaches for FRDA are aimed at restoring mitochondrial function, frataxin replacement or gene activation, and will at best slow or stop the progression of the disease without correcting existing neurological symptoms. Using recently developed gene manipulation methods, we will excise or correct the trinucleotide repeats from the FXN gene in FRDA patient stem cells (induced pluripotent stem cells). We will demonstrate that the corrected genes are active and produce normal levels of frataxin protein. Corrected FRDA stem cells will be differentiated into neurons in the laboratory, and the neurons will be tested for restoration of energy production in cells. Collaborative studies will focus on delivery of corrected neurons into FRDA mouse models to establish efficacy in reversing neurological symptoms.
Our efforts are aimed at development of novel stem cell-based therapeutics for a class of inherited neurological diseases, called triplet-repeat neurodegenerative diseases, which include Huntington’s disease, the spinocerebellar ataxias, forms of muscular dystrophy, Fragile X syndrome and Friederich’s ataxia (FRDA). These diseases, although relatively rare compared to cancer or heart disease, affect thousands of individuals in California. Recent advances now make it possible to generate induced pluripotent stem cells (iPSCs) from affected individuals and differentiate these cells into cell types that are at risk in these diseases (such as neurons, heart, and muscle cells), We will use state-of-the-art genetic manipulation methods to correct the causative mutation in FRDA iPSCs, and show that the corrected gene now functions normally. Neurons will be generated from these genetically corrected cells and used for transplantation into mouse models of FRDA. Restoration of neurological function in these animals will provide a proof of principal that such cells should be used in human clinical trials. Our studies may yield a new therapeutic approach for these currently untreatable disorders, which will be of benefit to patients suffering from these diseases, both in California and worldwide.