Weill Cornell scientists seek cure for Huntington's via 'designer mice'

By Sean Kelliher

By tweaking a gene in the mouse genome, scientists are creating animal models of Huntington's disease that mimic human Huntington's and may lead to effective treatments for this killer illness.

"I am heartened by this research because when I started out in this area maybe 25 years ago, we really didn't have any agents to try in patients. Now, if you look down the list, we have 15 to 20 different agents that we can eventually test in humans," said Dr. M. Flint Beal, the Anne Parrish Titzell Professor of Neurology and chairman of neurology and neuroscience at Weill Cornell Medical College. Beal also is neurologist-in-chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Beal's review of advances in Huntington's research using genetically engineered mice appears in a recent issue of Nature Reviews/Neuroscience.

Huntington's disease is caused by a mutation in the huntingtin gene that makes it repeat long sections of specific genetic code. Those repeats lead to serious dysfunctions within neural cells that end in the early death of cells in specific brain areas.

Symptoms of Huntington's include involuntary muscle movement as well as progressive mental deterioration leading to dementia. The disease can take decades to progress but is uniformly fatal. Currently, there is no effective treatment for Huntington's disease.

Because disease progression is so slow in humans, research into Huntington's has been stymied by a lack of good animal models. However, capitalizing on the recent completion of the mouse genome, neuroscientists in laboratories around the world now have engineered "transgenic mice" -- mice in which the huntingtin gene has been manipulated or replaced to produce rodent strains that closely mimic the disease in humans.

Previous Huntington's research had relied on nonmammalian models such as the worm or fruit fly, "but those other models aren't nearly as good as the transgenic mouse models," said Beal.

Neuroscientists have wasted no time in taking advantage of the half-dozen different transgenic Huntington mouse models now available. Because the origins of Huntington's disease are so complex, at least nine promising cellular targets for drug therapy are under investigation, Beal said.

"A really hot area right now is histone deacetylase (HDAC) inhibitors," he said. That family of drugs targets huntingtin-linked "transcriptional dysregulation" -- disruptions in gene replication caused by the mutant gene. In one recent study, HDAC inhibitors reduced shakiness and other symptoms in transgenic mice strains that mimicked human Huntington's.

Brain cell dysfunction caused by mutant huntingtin "also activates enzymes called transglutiminase," Beal noted. Those enzymes encourage an unhealthy clumping of proteins within the cell nucleus, also linked to early cell death. But in another study involving transgenic Huntington's mice, rodents injected with compounds called transglutaminase inhibitors lived significantly longer than those that didn't receive the therapy.

Most promising is the compound coenzyme Q10, which appears to reduce cell death by targeting "excitotoxicity" -- the increased activation of a specific receptor on the brain cell's surface. In transgenic mice trials conducted by Weill Cornell researchers, low-dose coenzyme Q10 "showed about a 14 percent slowing of disease progression," Beal said.

"We know now that doses higher than that are much more effective in Parkinson's patients, so we are right now planning a clinical trial using a much higher dose of coenzyme Q in patients with Huntington's disease," he said.

Beal's co-author on the article was Dr. Robert J. Ferrante of the Boston University School of Medicine.