Creatine Therapy for Huntington's Disease

Huntington's disease (HD) is a progressive and fatal neurologic disorder caused by an expanded CAG repeat in the gene coding for a protein of unknown function that has been named huntingtin. The exact cause of neuronal death in HD is unknown, however, the leading hypothesis is that of excitotoxicity and apoptosis induced by a defect in energy metabolism that may be caused by oxidative stress. We previously demonstrated that mitochondrial inhibitors produce striatal lesions closely mimicking the phenotype of HD. We have also shown that oxidative injury is involved in these models and may be in human HD. Because of this research, there has been increasing interest in the HD field in exploring complementary agents that might prevent oxidative injury, Creatine is a widely used dietary supplement principally taken to enhance athletic performance. It is a very strong candidate neuroprotective agent for HD and other neurodegenerative disorders because of its ability to ameliorate toxin-based animal models and because of our preliminary evidence in transgenic HD mice. However, there is only limited animal experience with creatine and there has not yet been any trials in humans with neurodegenerative disorders. There are several potential mechanisms by which creatine could be an effective treatment for HD. First, there is evidence that it can be neuroprotective by relieving oxidative stress. Second, it could directly inhibit apoptotic neuronal death through its inhibitory action on the mitochondrial transition pore. Third, we have preliminary evidence that creatine treatment may be associated with reduced huntingtin aggregation, a potentially toxic process. Finally it could act peripherally to help reverse the weakness and muscle mass loss that is a major clinical problem in HD. We have preliminary evidence that creatine can extend survival in transgenic models of HD and that it can reduce brain markers of metabolic stress in humans with HD. We propose to test whether creatine can ameliorate the behavioral and neuropathologic phenotypes occurring in transgenic models of HD, examine the potential mechanisms of creatine neuroprotection, test its safety and tolerability in HD patients, and collect pilot clinical data examining how creatine impacts HD symptoms and progression. These studies are intended to provide the basis of a subsequent phase III trial of creatine in HD.