Novel Method Results in Promising Drugs for Huntington's Disease Therapeutics

Buck Institute, Yale University and University of California, Berkeley scientists identify three caspase inhibitors that block HD-associated neuronal damage in cell culture; follow up experiments are underway in mice

Novato, CA November 24, 2010 Huntington's disease (HD) is an incurable progressive neurodegenerative genetic disorder which affects motor coordination and leads to cognitive decline and dementia.  The disease pathology stems from a mutation in the huntingtin (Htt) gene which results in the accumulation of toxic proteins leading to neuronal cell death.  Earlier studies have clearly implicated caspases, enzymes that break down cells, as key players in the cascade of events involved in HD neuronal death.  Now scientists have identified three small molecules that inhibit the activity of those caspases, suppressing toxicity and rescuing neurons from cell death in cell culture. The research, which appears in the November 24th edition of Chemistry and Biology, was led by both Buck Institute faculty member Lisa Ellerby, Ph.D. and Yale University faculty member Jonathan Ellman, Ph.D. Dr. Ellerby is doing follow up studies in a mouse model of the disease.

Dr. Ellerby said a substrate based screening method was used to identify compounds that reacted with caspases. Based on those reactions, Jonathan Ellman, Ph.D., from the Yale University Department of Chemistry, converted the compounds to caspase inhibitors.

Dr. Ellerby said that the inhibitors are based on properties of a drug which had entered Phase I clinical trials for the treatment of human liver preservation injury. "These molecules shows particular promise," said Ellerby. "They cross the blood-brain barrier and acts selectively to block the processes involved in HD." Dr. Ellerby said the caspase inhibitors both suppressed the proteolysis of Htt and rescued HD neurons that have begun to undergo cell death.

"We believe this is going to help us move the field forward because now we can test these compounds in live animals," said Dr. Ellerby. "Up until this point we have not identified a caspase inhibitor that has acted selectively against the toxic effects of the Htt mutation. There is a desperate need for a treatment for HD. Symptoms of the disease usually begin to occur in middle age; patients are often totally incapacitated prior to death.  The worldwide prevalence of HD is 5-10 cases per 100,000 people; the rate of occurrence is highest in peoples of Western European descent.

Other contributors to the work:
Other Buck Institute researchers involved in the study include Francesco DeGiacomo, Jennifer Holcomb, Ningzhe Zhang, and Juliette Gafni. The research also involved Melissa J. Leyva of the Department of Chemistry at the University of California, Berkeley and Linda S. Kaltenbach and Donald C. Lo of the Duke University Medical Center in Durham, NC. Other contributors included Hyunsun Park of the CHDI Foundation in Los Angeles, CA and Guy S. Salvesen of the Burnham Institute for Medical Research in La Jolla, CA. Jonathan Ellman of the Department of Chemistry at Yale University in New Haven, CT co-authored the study. The work was supported by grants from the National Institutes of Health, the CHDI Foundation and the Human Frontier Science Program.

About the Buck Institute for Age Research:
The Buck Institute is the only freestanding institute in the United States that is devoted solely to basic research on aging and age-associated disease. The Institute is an independent nonprofit organization dedicated to extending the healthspan, the healthy years of each individual’s life. Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating conditions such as Alzheimer’s and Parkinson’s disease, cancer and stroke.  Collaborative research at the Institute is supported by new developments in genomics, proteomics and bioinformatics technology.

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