Huntington's disease(HD), inherited in an autosomal dominant patterns, results from an excessive repetition of the CAG codon within the IT15 gene on the short arm of chromosome 4. HD is characterized clinically by inexorable functional decline and pathologically by selective and progressive degeneration of spiny neurons in the caudate and putamen (striatum). Experimental studies in animals have demonstrated that impairment of cellular mitochondrial energy metabolism or altered glutamatergic N- methyl-D-aspartate (NMDA) receptor-mediated activity, alone or in combination, can produce neuropathologic changes closely resembling HD. Ingestion of a mitochondrial toxin causes a similar clinical disease in humans and similar brain region and neuronal specific injury as in HD. Interventions that buttress mitochondrial energy metabolism and scavenge free radicals, such as co-enzyme Q10, or that block NMDA receptor activation, such as remacemide hydrochloride have been shown to attenuate these HD-like neuropathological changes. In HD patients, elevation in brain lactate in the cortex and basal ganglia can be demonstrated and measured by magnetic resonance (MR) spectroscopy. Elevated brain lactate occurs in other conditions characterized by impaired oxidative metabolism or excessive excitatory neurotransmission. In the HD post-mortem brain, striatal spiny neurons expressing NMDA receptors are selectively depleted. Although the mechanism of cell death caused by the expanded glutamine stretch in the HD protein product remain unknown, recent findings strongly suggest that both bioenergetic and glutamate-mediated mechanisms of cell injury may be involved in the pathogenesis of HD. Our preliminary studies of co-enzyme Q10 and of remacemide hydrochloride indicate that these agents are safe and well tolerated in HD patients and seem to slow the rate of functional decline. We hypothesize that chronic treatment of HD patients with co-enzyme Q10 and remacemide hydrochloride, alone or in combination, will slow the functional decline of HD. We plan to test this hypothesis by conducting a double-blind, placebo-controlled, randomized, parallel group, multi-center study of co-enzyme Q10 and remacemide hydrochloride using a 2x2 factorial design. The primary outcome measure will be the progression of HD as measured by the change in total functional capacity (TFC) between baseline and 30 months of treatment. With a sample size of 340 ambulatory HD patients who are treated for 30 months, we have greater than 80% power to detect meaningful therapeutic effects. Secondary treatment outcomes will include changes in the motor, cognitive, and behavioral components of the United Huntington's Disease Rating Scale (UHDRS) and changes in brain lactate as measured by MR spectroscopy. Twenty one research sites of the Huntington Study Group (HSG), under the direction of the principal investigator, steering committee, and advisory/monitoring committees, will conduct the controlled clinical trial.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurological Disorders Program Project Review A Committee (NSPA)
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Oliver, Eugene J
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University of Rochester
Schools of Dentistry
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