Stem Cell Breakthrough for Huntington's Disease

University of Rochester Medical Center, September 26, 2007

There may be new hope for individuals suffering from Huntington's disease -- a fatal disorder for which there is currently no cure or even a treatment to slow the disease. A new avenue of research has been opened by scientists who were sparked by an odd biological phenomenon: how a canary learns a new song.

Stem-cell therapy might someday be used to treat the disease according to scientists at the University of Rochester Medical Center. The Journal of Clinical Investigation published their paper on September 20th.

In the brains of mice affected by a form of Huntington's, the team used gene therapy to guide the development of endogenous stem cells. Many more new, viable brain cells as well as significantly longer and healthier lives characterized the treated mice. This was in stark contrast to the their non-treated counterparts.

Neurologist Steven Goldman, M.D., Ph.D., the lead author of the study said that the study offers a new approach in the fight against Huntington's, but that it is too early to predict whether such a treatment might work in people. The knowledge of the defective gene hasn't yet translated to better care for patients despite scientists being aware of the gene for more than a decade.

"There isn't much out there right now for patients who suffer from this utterly devastating disease," said Goldman, who is at the forefront developing new techniques to try to bring stem-cell therapy to the bedside of patients. "While the promise of stem cells is broadly discussed for many diseases, it's actually conditions like Huntington's -- where a very specific type of brain cell in a particular region of the brain is vulnerable -- that are most likely to benefit from stem-cell-based therapy."

The lead authors of the latest paper are former post-doctoral associate Sung-Rae Cho, Ph.D., now at Yonsei University in South Korea, and Abdellatif Benraiss, Ph.D., research assistant professor at the University of Rochester Medical Center.

The latest results have their roots in research Goldman did more than 20 years ago as a graduate student at Rockefeller University. Goldman discovered that every time a canary learns a new song, it creates new brain cells called neurons. He was doing basic neuroscience studies and investigating how exactly canaries learn new songs. His doctoral thesis opened the door to the possibility that the brain has a font of stem cells that could serve as the source for new cells. His 1983 thesis was also the first report of neurogenesis -- the production of new brain cells -- in the adult brain.

The finding led to a career for Goldman, who has created ways to isolate stem cells. Goldman's group has learned how to re-create signals to direct the cells' development. These molecular signals that help determine what specific types of cells they become were also discovered by Goldman thanks to their innovative techniques.

Benraiss has worked closely with Goldman for more than 10 years on the Huntington's project.

"The type of brain cell that allows a canary to learn a new song is the same cell type that dies in patients with Huntington's disease," said Goldman, professor of Neurology, Neurosurgery, and Pediatrics, and chief of the Division of Cell and Gene Therapy. "Once we worked out the molecular signals that control the development of these brain cells, the next logical step was to try to trigger their regeneration in Huntington's disease."

Affecting about 30,000 people in the United States, Huntington's is an inherited disorder. The condition results in depression, irritability, cognitive difficulties, problems with coordination, and involuntary movements. These symptoms can be contributed to a defective gene which results in the death of vital brain cells known as medium spiny neurons. When patients reach their 30's or 40's, the young to mid adulthood range, symptoms usually begin to appear. The disease is fatal and their is currently no way to slow the progression of the disease.

Scientists must learn the extensive molecular signaling that shapes their development before stem cells can be used to replace neurons lost in Huntington's and almost any disease. In the brain, a stem cell might become a medium spiny neuron or a dopamine-producing neuron to replace the cells destroyed by Huntington's or Parkinson's. However, the fate of the stem cells depends on a tremendous number of biochemical signals.

To replace those that had become defective in mice with the disease, Goldman's team set up a one-two molecular punch as a recipe for generating new medium spiny neurons. Extra copies of two genes were carried into a region of the mouse brain called the ventricular wall, which is home to stem cells. This was achieved by using a cold virus known as adenovirus. The neostriatum, which is affected by Huntington's disease, is very close to the ventricular wall which was the final destination for the stem cells.

To help stop stem cells from becoming another type of cell in the brain, an astrocyte, extra copies of a gene called Noggin were used. To help the stem cells to become neurons, they also put in extra copies of the gene for BDNF (brain-derived neurotrophic factor). Basically, stem cells were bathed in a brew that had extra Noggin and BDNF to direct their development into medium spiny neurons.

The results were dramatic in the mice which had a severe form of Huntington's disease. Compared to no new neurons in mice that weren't treated, several thousand newly formed medium spiny neurons were observed in the neostriatum when the treatment mice were examined. The treated mice were more coordinated, active, and healthier for a significantly longer period of time compared to the untreated mice. They lived about 17 percent longer compared to the untreated mice.

The experiment was designed to test the idea that scientists could generate new medium spiny neurons in an organism where those neurons had already become sick. Goldman is working on ways to extend the duration of the improvement now that the capability has been demonstrated. Treatment in patients is the ultimate goal for the future.

"This offers a strategy to restore brain cells that have been lost due to disease. That could perhaps be coupled with other treatments currently under development," said Goldman. Many of those treatments are being studied at the University, which is home to a Huntington's Disease Center of Excellence and is the base for the Huntington Study Group.

In addition to Benraiss, Cho, and Goldman, other authors include former Cornell graduate student Eva Chmielnicki, Ph.D.; Johns Hopkins neurosurgeon Amer Samdani, M.D., now at Shriners Children's Hospital in Philadelphia; and Aris Economides of Regeneron Pharmaceuticals. The work was funded by the National Institute of Neurological Disorders and Stroke, the Hereditary Disease Foundation, and the High Q Foundation.