This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that results from an unstable expansion of the trinucleotide repeat CAG in the gene IT-15, or Huntington, on chromosome 4. The clinical features of HD usually emerge in adulthood (mean age of 37 years) with chorea, disorders of voluntary movement, intellectual dysfunction, and psychiatric symptoms. HD is relentless, leading to functional disability and death over a period of 10-30 years. Approximately 30,000 people in the United States have clinical manifestations of HD, and an additional 150,000 healthy people are thought to be immediately at risk to develop HD. Although the precise mechanism by which the HD mutation causes disease is unknown, there is increasing experimental and pathologic evidence that brain cells in HD die as a result of an underlying energetic defect coupled with oxidative damage. Creatine, a dietary supplement that may improve bioenergetics and reduce oxidative stress, is thought to have a potential to protect neurons and has been shown to significantly prolong survival in two different mouse models of HD. However, there is little controlled data about the safety and tolerability of long-term creatine use in normal or ill populations. We have recently completed a double blind, placebo-controlled Phase II clinical trial (CREST-HD) examining 8-gram daily creatine taken by subjects with HD over four months. Although the blind will not be broken for some months, creatine at this dose was completely safe and tolerable with no adverse experiences related to study drug. While evidence for possible efficacy cannot be assessed until the blind is broken, anecdotally many subjects feel they have benefited from study drug and wish to continue. Therefore, we propose an extension to CREST-HD, the primary purpose of which is to find the maximally tolerated dose of creatine that is safe and tolerable in subjects with HD. In addition, this study will serve to lay the essential groundwork for a future Phase III (efficacy) clinical trials designed to specifically address creatine's ability to slow or halt the progression of HD at the maximally tolerated dose.
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