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Turning Skin Cells Into Brain Cells
Release Date: 06/28/2012
Researchers create "Huntington's disease in a dish" to enable search for
Johns Hopkins researchers, working with an international consortium, say
they have generated stem cells from skin cells from a person with a severe,
early-onset form of Huntington's disease (HD), and turned them into neurons
that degenerate just like those affected by the fatal inherited disorder.
By creating "HD in a dish," the researchers say they have taken a major step
forward in efforts to better understand what disables and kills the cells in
people with HD, and to test the effects of potential drug therapies on cells
that are otherwise locked deep in the brain.
Although the autosomal dominant gene mutation responsible for HD was
identified in 1993, there is no cure. No treatments are available even to
slow its progression.
The research, published in the journal Cell Stem Cell, is the work of a
Huntington's Disease iPSC Consortium, including scientists from the Johns
Hopkins University School of Medicine in Baltimore, Cedars-Sinai Medical
Center in Los Angeles and the University of California, Irvine, as well as
six other groups. The consortium studied several other HD cell lines and
control cell lines in order to make sure results were consistent and
reproducible in different labs.
The general midlife onset and progressive brain damage of HD are especially
cruel, slowly causing jerky, twitch-like movements, lack of muscle control,
psychiatric disorders and dementia, and - eventually - death. In some cases
(as in the patient who donated the material for the cells made at Johns
Hopkins), the disease can strike earlier, even in childhood.
"Having these cells will allow us to screen for therapeutics in a way we
haven't been able to before in Huntington's disease," saysChristopher A.
Ross, M.D., Ph.D., a professor of psychiatry and behavioral sciences,
neurology, pharmacology and neuroscience at the Johns Hopkins University
School of Medicine and one of the study's lead researchers. "For the first
time, we will be able to study how drugs work on human HD neurons and
hopefully take those findings directly to the clinic."
Ross and his team, as well as other collaborators at Johns Hopkins and Emory
University, are already testing small molecules for the ability to block HD
iPSC degeneration. These small molecules have the potential to be developed
into novel drugs for HD.
The ability to generate from stem cells the same neurons found in
Huntington's disease may also have implications for similar research in
other neurodegenerative diseases such as Alzheimer's and Parkinson's.
To conduct their experiment, Ross took a skin biopsy from a patient with
very early onset HD. When seen by Ross at the HD Center at Hopkins, the
patient was just seven years old. She had a very severe form of the disease,
which rarely appears in childhood, and of the mutation that causes it. Using
cells from a patient with a more rapidly progressing form of the disease
gave Ross' team the best tools with which to replicate HD in a way that is
applicable to patients with all forms of HD.
Her skin cells were grown in culture and then reprogrammed by the lab of
Hongjun Song, Ph.D., a professor at Johns Hopkins' Institute for Cell
Engineering, into induced pluripotent stem cells. A second cell line was
generated in an identical fashion in Dr. Ross's lab from someone without HD.
Simultaneously, other HD and control iPS cell lines were generated as part
of the NINDS funded HD iPS cell consortium.
Scientists at Johns Hopkins and other consortium labs converted those cells
into generic neurons and then into medium spiny neurons, a process that took
three months. What they found was that the medium spiny neurons deriving
from HD cells behaved just as they expected medium spiny neurons from an HD
patient would. They showed rapid degeneration when cultured in the lab using
basic culture medium without extensive supporting nutrients. By contrast,
control cell lines did not show neuronal degeneration.
"These HD cells acted just as we were hoping," says Ross, director of the
Baltimore Huntington's Disease Center. "A lot of people said, 'You'll never
be able to get a model in a dish of a human neurodegenerative disease like
this.' Now, we have them where we can really study and manipulate them, and
try to cure them of this horrible disease. The fact that we are able to do
this at all still amazes us."
Specifically, the damage caused by HD is due to a mutation in the huntingtin
gene (HTT), which leads to the production of an abnormal and toxic version
of the huntingtin protein. Although all of the cells in a person with HD
contain the mutation, HD mainly targets the medium spiny neurons in the
striatum, part of the brain's basal ganglia that coordinates movement,
thought and emotion. The ability to work directly with human medium spiny
neurons is the best way, researchers believe, to determine why these
specific cells are susceptible to cell stress and degeneration and, in turn,
to help find a way to halt progression of HD.
Much HD research is conducted in mice. And while mouse models have been
helpful in understanding some aspects of the disease, researchers say
nothing compares with being able to study actual human neurons affected by
For years, scientists have been excited about the prospect of making
breakthroughs in curing disease through the use of stem cells, which have
the remarkable potential to develop into many different cell types. In the
form of embryonic stem cells, they do so naturally during gestation and
early life. In recent years, researchers have been able to produce induced
pluripotent stem cells (iPSCs), which are adult cells (like the skin cells
used in Ross's experiments) that have been genetically reprogrammed back to
the most primitive state. In this state, under the right circumstances, they
can then develop into most or all of the 200 cell types in the human body.
The other members of the research consortium include the University of
Wisconsin School of Medicine, Massachusetts General Hospital and Harvard
Medical School, the University of California, San Francisco, Cardiff
University the Universita degli Studi diMilano and the CHDI Foundation.
Primary support for this research came from an American Recovery and
Reinvestment Act (ARRA) grant (RC2-NS069422) from the National Institutes of
Health's National Institute of Neurological Disorders and Stroke and a grant
from the CHDI Foundation, Inc.
Other Johns Hopkins researchers involved in this study include Sergey
Akimov, Ph.D.; Nicolas Arbez, Ph.D.; Tarja Juopperi, D.V.M., Ph.D.; Tamara
Ratovitski; Jason H. Chiang; Woon Roung Kim; Eka Chighladze, M.S., M.B.A.;
Chun Zhong; Georgia Makri; Robert N. Cole; Russell L. Margolis, M.D.; and
Guoli Ming, M.D., Ph.D.
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