Stem cells show promise for treating Huntington's disease
The song of the canary aids the quest to create medium spiny neurons
Paying close attention to how a canary learns a new song has helped
scientists open a new avenue of research against Huntington's
disease – a fatal disorder for which there is currently no cure or
even a treatment to slow the disease.
In a paper published Sept. 20 in the Journal of Clinical
Investigation, scientists at the University of Rochester Medical
Center have shown how stem-cell therapy might someday be used to
treat the disease. The team used gene therapy to guide the
development of endogenous stem cells in the brains of mice affected
by a form of Huntington's. The mice that were treated lived
significantly longer, were healthier, and had many more new, viable
brain cells than their counterparts that did not receive the
treatment.
While it's too early to predict whether such a treatment might work
in people, it does offer a new approach in the fight against
Huntington's, says neurologist Steven Goldman, M.D., Ph.D., the lead
author of the study. The defective gene that causes the disease has
been known for more than a decade, but that knowledge hasn't yet
translated to better care for patients.
"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 Abdellatif Benraiss, Ph.D.,
research assistant professor at the University, and former post-
doctoral associate Sung-Rae Cho, Ph.D., now at Yonsei University in
South Korea.
The latest results have their roots in research Goldman did more than
20 years ago as a graduate student at Rockefeller University. In
basic neuroscience studies, Goldman was investigating how canaries
learn new songs, and he found that every time a canary learns a new
song, it creates new brain cells called neurons. His doctoral thesis
in 1983 was the first report of neurogenesis – the production of new
brain cells – in the adult brain, and opened the door to the
possibility that the brain has a font of stem cells that could serve
as the source for new cells.
The finding led to a career for Goldman, who has created ways to
isolate stem cells. These techniques have allowed Goldman's group to
discover the molecular signals that help determine what specific
types of cells they become, and re-create those signals to direct the
cells' development. 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."
Huntington's is an inherited disorder that affects about 30,000
people in the U.S. A defective gene results in the death of vital
brain cells known as medium spiny neurons, resulting in involuntary
movements, problems with coordination, cognitive difficulties, and
depression and irritability. The disease usually strikes in young to
mid adulthood, in a patient's 30s or 40s; there is currently no way
to slow the progression of the disease, which is fatal.
Stem cells offer a potential pool to replace neurons lost in almost
any disease, but first scientists must learn the extensive molecular
signaling that shapes their development. The fate of a stem cell
depends on scores of biochemical signals – in the brain, a stem cell
might become a dopamine-producing neuron, perhaps, or maybe a medium
spiny neuron, cells that are destroyed by Parkinson's and
Huntington's diseases, respectively.
To do this work, Goldman's team set up a one-two molecular punch as a
recipe for generating new medium spiny neurons, to replace those that
had become defective in mice with the disease. The team used a cold
virus known as adenovirus to carry extra copies of two genes into a
region of the mouse brain, called the ventricular wall, that is home
to stem cells. This area happens to be very close to the area of the
brain, known as the neostriatum, which is affected by Huntington's
disease.
The team put in extra copies of a gene called Noggin, which helps
stop stem cells from becoming another type of cell in the brain, an
astrocyte. They also put in extra copies of the gene for BDNF (brain-
derived neurotrophic factor), which helps stem cells become neurons.
Basically, stem cells were bathed in a brew that had extra Noggin and
BDNF to direct their development into medium spiny neurons.
The results in mice, which had a severe form of Huntington's disease,
were dramatic. The mice had several thousand newly formed medium
spiny neurons in the neostriatum, compared to no new neurons in mice
that weren't treated, and the new neurons formed connections like
medium spiny neurons normally do. The mice lived about 17 percent
longer and were healthier, more active and more coordinated
significantly longer than 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. Now that the capability has been
demonstrated, Goldman is working on ways to extend the duration of
the improvement. Ultimately he hopes to assess this potential
approach to treatment in patients.
"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,
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.
Public release date: 25-Sep-2007
Contact: Tom Rickey
tom_rickey@urmc.
585-275-7954
University of Rochester Medical Center
http://www.eurekale
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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