A compound developed by researchers at Vanderbilt University can improve early symptoms and delay progression of Huntington’s disease in a mouse model of the neurodegenerative disorder.
The findings, reported this week in the Proceedings of the National Academy of Sciences, offer one of the first glimmers of hope for a way to treat the rare genetic disease, which killed folksinger Woody Guthrie in 1967 at age 55.
“We are very excited by the results of this study,” said Jeffrey Conn, Ph.D., director of the Vanderbilt Center for Neuroscience Drug Discovery and lead investigator on the study.
“At present, there is no effective treatment for this devastating disorder,” Conn said. “Any advance that could help reduce suffering of these patients would have a tremendous impact.”
In its early stages, Huntington’s disease affects muscle coordination and causes changes in personality and behavior. As the disease progresses, patients experience cognitive decline, psychiatric symptoms, involuntary muscle contractions, difficulty moving and ultimately death.
At the cellular level, the disease is characterized by the presence of a mutant protein, called mutant Htt, which causes an abnormal increase in the transmission of signals across the synapse, or gap, between certain nerve cells in the some parts of the brain.
A type of muscarinic acetylcholine receptor called M4, which binds the neurotransmitter acetylcholine, can block these signals. The Vanderbilt researchers reasoned that selective activation of M4, therefore, should normalize excessive transmission caused by Huntington’s disease.
Their hunch was correct.
Using a compound called a positive allosteric modulator or PAM, which — like the dimmer switch in an electrical circuit — can turn up the activity of M4, the researchers showed that they could completely counteract early deficits in neuronal transmission in a mouse model of the disease.
Motor function also improved in the young animals.
The compound thus provides a potential therapeutic approach that could slow the progression of the disease, the researchers concluded.
M4 PAMs also may improve certain cognitive impairments and behavioral disturbances associated with neuropsychiatric disorders including Alzheimer’s disease and schizophrenia. Vanderbilt scientists are working with the pharmaceutical company AstraZeneca to advance these compounds into clinical testing in Alzheimer’s patients, said Conn, the Lee E. Limbird Professor of Pharmacology.
“These studies could provide a basis for expanding the clinical plan to also evaluate potential efficacy of these compounds in Huntington’s patients,” he said.
Conn and Zixiu Xiang, Ph.D., research assistant professor of Pharmacology, led the research team. Research fellow Triscano Pancani, Ph.D., was first author of the paper.
Other Vanderbilt faculty members who contributed to the study were Craig Lindsley, Ph.D., Aaron Bowman, Ph.D., Michael Wood, Ph.D., Carrie Jones, Ph.D., Colleen Niswender, Ph.D., J. Scott Daniels, Ph.D., Jerri Rook, Ph.D., and Thomas Bridges, Ph.D.
The research was supported in part by National Institutes of Health grants MH067965, NS065867, NS071669 and ES016931.