Ursodiol in Huntington's Disease (UDCA-HD)

The purpose of this study is to evaluate the safety of the drug ursodiol (ursodeoxycholic acid, UDCA) in people with Huntington's disease (HD) and to explore how the compound is processed by the body.

Huntington's disease is an inherited neurodegenerative disease that causes a movement disorder, dementia, and psychiatric and behavioral disturbance in affected individuals. Tauroursodeoxycholic acid (TUDCA) is a bile acid synthesized in the liver by the conjugation of taurine to ursodeoxycholic acid (UDCA). It is thought to function as an anti-apoptotic agent in HD, evidenced by studies in toxic cell models and both toxic and transgenic rodent models of the disease. Ursodiol is a commercially-available exogenous form of UDCA, the precursor of TUDCA. Although the compound has an established dosing, safety, tolerability and efficacy profile in patients with hepatobiliary disorders, gaps exist in the understanding of the pharmacokinetics / pharmacodynamics of the compound, particularly in patients with normal gastrointestinal function, and no human data exist for its therapeutic use in neurodegenerative disorders. The specific aims of this study are: To establish whether treatment with the drug ursodiol will result in measurable levels of its bile acid metabolites in serum and CSF at standard oral doses; and whether a dose-response can be detected using these measures. To establish a preliminary safety and tolerability profile of the drug in subjects with HD.

ursodiol 300 mg twice daily for study days 0 through 28 ursodiol 600mg twice daily on study days 0 through 28

Inclusion Criteria: All subjects will be age 18 or older All subjects will have manifest Huntington disease determined by clinical exam plus either documented prior DNA testing for the HD gene or a documented family history of the disease Exclusion Criteria: Subjects taking oral contraceptives, cholestyramine, colestipol, or aluminum-based antacids will be excluded Subjects with known allergy or other contraindication to the study drug will be excluded Subjects with bleeding diathesis, or on coumadin or mandatory aspirin will be excluded Subjects with unstable medical or psychiatric illness will be excluded Subjects with clinically significant lab / EKG abnormalities at screening will be excluded Subjects who are currently pregnant or breastfeeding will be excluded

Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10671-6. doi: 10.1073/pnas.162362299. Epub 2002 Jul 29.

Keene CD, Rodrigues CM, Eich T, Linehan-Stieers C, Abt A, Kren BT, Steer CJ, Low WC. A bile acid protects against motor and cognitive deficits and reduces striatal degeneration in the 3-nitropropionic acid model of Huntington's disease. Exp Neurol. 2001 Oct;171(2):351-60. doi: 10.1006/exnr.2001.7755.