"Designer Mice" Yielding Up Secrets Of Huntington's Disease, Says Weill Cornell Neuroscientist

"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, in New York City. Dr. Beal is also Neurologist-in-Chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Dr. 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 causes it to repeat long sections of specific genetic code. These 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. Disease progression can take decades and is uniformly fatal. At this point in time, 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 labs around the world have now engineered "transgenic mice" — mice in which the huntingtin gene has been manipulated or replaced to produce rodent strains that closely mimic human disease.

Previous Huntington's research had relied on non-mammalian models such as the worm or fruit fly, "but those other models aren't nearly as good as the transgenic mouse models," according to Dr. Beal.

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

"A really hot area right now is histone deacetylase (HDAC) inhibitors," he said. This 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," Dr. Beal noted. These 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% slowing of disease progression," Dr. Beal said.

"We know now that doses that are 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.

Dr. Beal cautioned that there's probably no single agent out there to cure an illness as complex as Huntington's. Instead, Huntington's patients will probably be prescribed a combination of drugs, each aimed at a different target, in the same way that patients with HIV infection or cancer are treated today.

"I think that will happen for Huntington's disease, too," he said. "I don't think we'll find one magic bullet."

Dr. Beal co-authored the review article with Dr. Robert J. Ferrante of the Boston University School of Medicine.