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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,” 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.

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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.

Contact: Tom Rickey
tom_rickey@urmc.rochester.edu
585-275-7954
University of Rochester Medical Center

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September 25, 2007 Posted by | Global Health Vision, Global News, Huntington's disease, Journal of Clinical Investigation, RSS Feed, Stem Cells, University of Rochester | 3 Comments

Embryonic stem cells used to grow cartilage

Rice method is first to yield cartilage-like cells, engineer human cartilage

HOUSTON, Sept. 6, 2007 – Rice University biomedical engineers have developed a new technique for growing cartilage from human embryonic stem cells, a method that could be used to grow replacement cartilage for the surgical repair of knee, jaw, hip, and other joints.

“Because native cartilage is unable to heal itself, researchers have long looked for ways to grow replacement cartilage in the lab that could be used to surgically repair injuries,” said lead researcher Kyriacos A. Athanasiou, the Karl F. Hasselmann Professor of Bioengineering. “This research offers a novel approach for producing cartilage-like cells from embryonic stem cells, and it also presents the first method to use such cells to engineer cartilage tissue with significant functional properties.”

The results are available online and slated to appear in the September issue of the journal Stem Cells. The study involved cells from an NIH-sanctioned stem cell line.

Using a series of stimuli, the researchers developed a method of converting the stem cells into cartilage cells. Building upon this work, the researchers then developed a process for using the cartilage cells to make cartilage tissue. The results show that cartilages can be generated that mimic the different types of cartilage found in the human body, such as hyaline articular cartilage — the type of cartilage found in all joints — and fibrocartilage — a type found in the knee meniscus and the jaw joint. Athanasiou said the results are exciting, as they suggest that similar methods may be used to convert the stem cell-derived cartilage cells into robust cartilage sections that can be of clinical usefulness.

Tissue engineers, like those in Athanasiou’s research group, are attempting to unlock the secrets of the human body’s regenerative system to find new ways of growing replacement tissues like muscle, skin, bone and cartilage. Athanasiou’s Musculoskeletal Bioengineering Laboratory at Rice University specializes in growing cartilage tissues.

The idea behind using stem cells for tissue engineering is that these primordial cells have the ability to become more than one type of cell. In all people, there are many types of “adult” stem cells at work. Adult stem cells can replace the blood, bone, skin and other tissues in the body. Stem cells become specific cells based upon a complex series of chemical and biomechanical cues, signals that scientists are just now starting to understand.

Unlike adult stem cells, which can become only a limited number of cell types, embryonic stem cells can theoretically become any type of cell in the human body.

Athanasiou’s group has been one of the most successful in the world at studying cartilage cells and, especially, engineering cartilage tissues. He said that for his research the primary advantage that embryonic stem cells have over adult stem cells is their ability to remain malleable.

“Identifying a readily available cell source has been a major obstacle in cartilage engineering,” Athanasiou said. “We know how to convert adult stem cells into cartilage-like cells. The more problematic issue comes in trying to maintain a ready stock of adult stem cells to work with. These cells have a strong tendency to convert from stem cells into a more specific type of cell, so the clock is always ticking when we work with them.”

By contrast, Athanasiou said his research group has found it easier to grow and maintain a stock of embryonic stem cells. Nonetheless, he is quick to point out that there is no clear choice about which type of stem cell works best for cartilage engineering.

“We don’t know the answer to that,” Athanasiou said. “It’s extremely important that we study all potential cell candidates, and then compare and contrast those studies to find out which works best and under what conditions. Keep in mind that these processes are very complicated, so it may well be that different types of cells work best in different situations.”

Athanasiou began studying embryonic stem cells in 2005. Since funding for the program was limited, he asked two new graduate students in his group if they were interested in pursuing the work as a secondary project to their primary research. Those students, Eugene Koay and Gwen Hoben, are co-authors of the newly published study. Both are enrolled in the Baylor College of Medicine Medical Scientist Training Program, a joint program that allows students to concurrently earn their medical degree from Baylor while undertaking Ph.D. studies at Rice.

“Eugene and Gwen are both outstanding students,” Athanasiou said. “Each earned their undergraduate degree from Rice and each worked in my laboratory as undergraduate students. They have chosen to do this research because they think this may represent the future of regenerative medicine.”

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The research was funded by Rice University.

Contact: Jade Boyd
jadeboyd@rice.edu
713-348-6778
Rice University

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September 7, 2007 Posted by | Global Health Vision, Global News, Health, Health Canada, HIV, Hospital Epidemiology, News UK, News USA, RSS, Science, Stem Cells | Leave a comment

UCI launches effort to develop patient-specific stem cell lines

UC Irvine neurobiologist Hans Keirstead and his research team today launched a project to develop stem cell lines that genetically match human patients. These lines would allow scientists to better study conditions ranging from diabetes to Parkinson’s disease, and they would provide the basis for potential patient-specific stem cell treatments.

Contact: Jennifer Fitzenberger
jfitzen@uci.edu
949-824-3969
University of California – Irvine

May 14, 2007 Posted by | Global, Global Health Vision, Global News, Irvine, News, News Australia, News Canada, News UK, News US, Parkinson's, Stem Cells, University of California, Washington DC | Leave a comment