Monday, December 14, 2009

New Hope for Brain, Spinal Cord Injuries

Deletion of key gene could help nerve fibers regenerate, researchers say


Deleting a gene that suppresses natural growth factors enables regeneration of injured nerve fibers (axons) in mice, a new study shows.

The finding may lead to new treatments for people with brain and spinal cord injuries.

Researchers at Children's Hospital Boston deleted the gene SOCS3 -- an inhibitor of a growth pathway called mTOR -- in the retinal ganglion cells of mice. These cells are in the optic nerve, which carries signals from the eyes to the brain.

Removel of SOCS3 resulted in vigorous growth of injured axons. The greatest improvement was seen after one week, when the researchers also detected signs that the mTOR pathway was re-activated. Axon growth increased even more when the researchers applied a growth factor called ciliary neurotrophic factor (CNTF) directly to the eye of mice in which SOCS3 had been deleted. But CNTF only modestly boosted axon growth in mice that still had SOCS3.

"CNTF and other cytokines [cellular signaling molecules] have been tested for promoting axon regeneration previously, but with no success," study leader Zhigang He, of the F.M. Kirby Neurobiology Center at Children's Hospital Boston, said in a university news release. "Now we know that this is due to the tight negative control of SOCS3. Inhibiting SOCS3, using small molecule compounds or RNA interference, might allow these cytokine growth factors to be functional."

The study appears in the Dec. 10 issue of Neuron.

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Monday, September 21, 2009

Scientists Make Paralyzed Rats Walk Again After Spinal Cord Injury

UCLA researchers have discovered that a combination of drugs, electrical stimulation and regular exercise can enable paralyzed rats to walk and even run again while supporting their full weight on a treadmill.

Published Nov. 20 in the online edition of Nature Neuroscience, the findings suggest that the regeneration of severed nerve fibers is not required for paraplegic rats to learn to walk again. The finding may hold implications for human rehabilitation after spinal cord injuries.

"The spinal cord contains nerve circuits that can generate rhythmic activity without input from the brain to drive the hind leg muscles in a way that resembles walking called 'stepping,'" explained principal investigator Reggie Edgerton, a professor of neurobiology and physiological sciences at the David Geffen School of Medicine at UCLA.

"Previous studies have tried to tap into this circuitry to help victims of spinal cord injury," he added. "While other researchers have elicited similar leg movements in people with complete spinal injuries, they have not achieved full weight-bearing and sustained stepping as we have in our study."

Edgerton's team tested rats with complete spinal injuries that left no voluntary movement in their hind legs. After setting the paralyzed rats on a moving treadmill belt, the scientists administered drugs that act on the neurotransmitter serotonin and applied low levels of electrical currents to the spinal cord below the point of injury.

The combination of stimulation and sensation derived from the rats' limbs moving on a treadmill belt triggered the spinal rhythm-generating circuitry and prompted walking motion in the rats' paralyzed hind legs.

Daily treadmill training over several weeks eventually enabled the rats to regain full weight-bearing walking, including backwards, sideways and at running speed. However, the injury still interrupted the brain's connection to the spinal cord-based rhythmic walking circuitry, leaving the rats unable to walk of their own accord.

Neuro-prosthetic devices may bridge human spinal cord injuries to some extent, however, so activating the spinal cord rhythmic circuitry as the UCLA team did may help in rehabilitation after spinal cord injuries.

The study was funded by the Christopher and Dana Reeve Foundation, Craig Nielsen Foundation, National Institute of Neurological Disorders and Stroke, U.S. Civilian Research and Development Foundation, International Paraplegic Foundation, Swiss National Science Foundation and the Russian Foundation for Basic Research Grants.

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Tuesday, July 28, 2009

Stem-Cell Breakthrough

It's a chilling thought. In the coming year, 130,000 people worldwide will suffer spinal-cord injuries?in a car crash, perhaps, or a fall. More than 90 percent of them will endure at least partial paralysis. There is no cure. But after a decade of hype and controversy over research on embryonic stem cells?cells that could, among other things, potentially repair injured spinal cords?the world's first clinical trial is about to begin. As early as this month, the first of 10 newly injured Americans, paralyzed from the waist down, will become participants in a study to assess the safety of a conservative, low-dose treatment. If all goes well, researchers will have taken a promising step toward a goal that once would have been considered a miracle?to help the lame walk.

The trial signals a new energy permeating the field of stem-cell research. More than 3,000 scientists recently met in Barcelona for the annual conference of the International Society for Stem Cell Research, compared with just 600 researchers five years ago. Money from major pharmaceutical companies is following the advances. Former U.S. vice president Al Gore, now a partner in the venture-capital firm Kleiner Perkins Caufield & Byers, has thrown his weight behind the research. In April, the firm joined with Highland Capital Partners to invest $20 million in iZumi Bio (now iPierian), a startup firm working on stem-cell therapies.
Click here to find out more!

Despite the considerable hype surrounding stem cells in recent years, the possibilities now appear to be broader than most people realize. In addition to helping replace damaged cells in patients with diseases like diabetes or Parkinson's, stem cells have the potential to change how we develop drugs and unravel the biology of disease. They may even be used one day to create replacement organs. "There's been a massive injection of optimism into the field," says stem-cell biologist Alan Trounson, president of the California Institute for Regenerative Medicine. "It's remarkable how fast it's progressing."

Much of the excitement comes from the development of a new type of stem cells, called "induced pluripotent" stem cells, or iPS. Shinya Yamanaka first concocted the cells in his Kyoto University lab by inserting four genes into fully formed adult skin cells. They began to behave like embryonic stem cells, capable of forming unlimited copies of any of the body's 220 cell types. Because iPS cells can be derived from a patient's own adult cells, they do not carry the risk of rejection by the immune system. Equally important, because iPS cells are not derived from embryos, they skirt a major ethical and religious problem.

The first iPS cells, however, will not be used as replacement tissue for spinal cords and other organs. Because iPS cells have subtle (and potentially dangerous) differences from true embryonic stem cells, many doctors are leery of putting them directly into patients until more research is done. But the cells could be immensely important in helping scientists understand and treat genetically based diseases.

By the time a full-blown disease has emerged, says Harvard stem-cell biologist Konrad Hochedlinger, it's like an airplane that has crashed. You can examine the wreckage for clues, but what you really want is the plane's black boxes?the flight-data and cockpit voice recorders that tell you exactly how electrical systems failed, hardware malfunctioned, and pilots made crucial errors. That's what doctors think iPS cells could provide. By coaxing some iPS cells into becoming the cell types affected in Huntington's disease, type 1 diabetes, or ALS (Lou Gehrig's disease), scientists will be able to watch in the lab as the disease unfolds. They'll be able to understand how the disease starts, which could lead to new ways of blocking it.

Embryonic stem cells are still regarded as the gold standard. That's why there is intense interest in the U.S. spinal-cord-injury trial. Sponsored by Geron Corp. in California, the trial will recruit patients within one to two weeks of their injuries, before scar tissue has formed. Doctors will inject a derivative of stem cells, called progenitor cells, that manufacture myelin, the substance that coats the long, spindly projections on nerve cells, much the same way that insulation coats electrical wires. Damage to cells that make and maintain the myelin sheath, as happens in spinal-cord injuries, prevents nerves from conveying messages from the brain. Although it's not clear yet whether the treatment is effective or safe, the restoration of even partial function would be a huge advance.

Geron's CEO, Dr. Thomas Okarma, thinks that spinal injury is a logical place to begin. Because patients will be completely paralyzed from the waist down, any improvement will be the result of the therapy, not chance. And the spinal cord is an "immune-privileged site," meaning that the attack cells of the immune system cannot get in and destroy the embryo-derived cells. "If the therapy is safe and effective, the potential impact will extend way beyond spinal-cord injury," says Okarma. "It will mark the start of a new era in medical therapeutics."

Other companies aren't waiting for the results. The U.S. pharmaceutical giant Pfizer is pursuing two other embryonic-stem-cell-based therapies, which it hopes to have in clinical trials by 2011. In April the company partnered with University College London to pursue a therapy for macular degeneration, the principal cause of blindness in the elderly. The disease leads to the gradual destruction of the macula, the sensitive central portion of the retina. But Peter Coffey, professor of cellular therapy and visual sciences at UCL, is using embryonic cells to make the same type of support cells that lie just behind the retina, providing it with nutrients. The goal is to implant a disc-shaped layer of the cells behind the retina. Immune rejection should not be a problem, since the eye is also immune-privileged.

Pfizer's other collaboration, with Novocell in California, aims to devise a treatment for some of the 100 million patients worldwide with insulin-dependent diabetes. Novocell is using embryonic stem cells to help regenerate all five of the pancreas's cell types. But there's a hitch. Unlike the eye or the spinal cord, the pancreas has no immune protection. For this, Novocell has devised a clever solution. It encases the stem-cell-derived progenitor cells in a capsule that can be implanted in the body. The pore size of the fabric is large enough to allow oxygen, glucose, and insulin to pass through but small enough to keep out big immune cells. "If problems should develop, the surgeon can easily remove the capsule," says Liz Bui, director of intellectual property for Novocell.

Some researchers aren't interested in just replacing impaired cells. They're using adult stem cells?which exist within organs to help with minor repairs?to grow entire replacement organs and tissues. Dr. Anthony Atala, director of the Institute for Regenerative Medicine at Wake Forest University in North Carolina, has made human bladders in this way. He starts by taking a small bladder biopsy from the patient and extracting his or her stem cells. After allowing the cells to multiply in the lab for about a month, he spreads them onto a collagen scaffold fashioned in the shape of a bladder. He then incubates the would-be organ in a bioreactor that provides the same temperature, oxygen level, growth factors, and nutrients that would be found in the body. In two weeks, he has a small but functional organ, ready for a patient.

In the early 2000s, Atala completed the procedure on seven children with spina bifida, who never developed fully functional bladders. He has now followed these patients for eight years to make sure there are no drastic failures or side effects. And he has moved on to other possible replacement parts. "We're working on 22 tissues and organs, including kidneys, heart valves, and cartilage," he says.

Because any new therapy is inherently risky, researchers are careful about creating false hopes that cures are just around the corner. Therapies that succeed in the idealized world of the lab can fail in real life or take decades to put into practice. As doctors and regulators begin to consider treating patients, they still have basic questions. Will the cells survive for long in the body? Will they integrate to form functioning tissue? Will the benefits outweigh risks that may become apparent only decades from now? Scientists are daring to hope, though, that after a decade of hype, real progress is imminent. Millions of patients worldwide could one day be the beneficiaries.

By Anne Underwood | NEWSWEEK

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Tuesday, December 16, 2008

Help Find A Cure for SCI!

By joining Find A Cure Panel?s exciting online research panel for people with spinal cord injuries, you will be empowered to share your personal experiences in vital research.

What's more, for each survey you complete a $10 donation is made directly to a worthy nonprofit organization in spinal cord injury research and support.

Registering is fast, free and your privacy is completely protected!

Registration Link: Find A Cure Panel

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Friday, November 21, 2008

Nose Cells May Heal Spinal Cord Injuries

People paralysed by spinal cord injuries could soon be "repaired" using cells from their own noses, say Otago University researchers.


The Health Ministry's ethics committee has just approved an application by the Spinal Cord Society to open the way for a clinical trial involving 12 patients, which could start next year.

The society's president, Noela Vallis, said there was no shortage of volunteers ready to take part.

"Some have already gone overseas out of a sense of frustration that they can't access it [the experimental treatment] here," Mrs Vallis said.

About 5000 Kiwis are in wheelchairs as a result of accidents - the highest rate of any country in the developed world.

Research director Jim Faed, who heads the the Spinal Cord Society's lab at Otago University, has spent five years developing laboratory methods for growing cells potentially useful for spinal cord injury repair.

His team is focusing on two promising cell types: one is a kind of adult stem cell produced by a patient's own bone marrow.

However, researchers are likely to begin trials using olfactory (scent receptor) cells from the patient's nose, injecting them into damaged spinal cord.

"The olfactory tissue in the nose is unique because it is the only place in the body where there is constant replacement of nerve cells throughout life," Dr Faed said.

"There is growing medical opinion that these cells can help overcome the blocks that prevent nerve cells regenerating after damage to the spinal cord."

The nasal tissue acts like "nurse cells", providing growth factor hormone to nerve cells, enabling them to make "meaningful connections".

Internationally, several research groups have done animal trials using the cells, but there has been only one human trial - in Portugal in 2006. The Otago group is in contact with Portuguese neuropathologist Carlos Lima, who pioneered that trial.

Dr Faed said some participants experienced side-effects, but they were "few and manageable" and none had been fatal.

Positive benefits for patients included return of some muscle function and sensation in parts of the body which previously had no feeling.

Dr Faed said the Dunedin lab hoped to get full approval for the trial before Christmas, and would then begin recruiting patients. The first 12 could start treatment next year.

Mrs Vallis - who founded the society after her late husband was paralysed in an accident - said the group aimed to raise $1 million to fund the trial, in addition to the $300,000 it finds every year to run the lab. "We should be at the forefront of developing this medical treatment, given the number of our citizens in wheelchairs."

Feilding man Iain Scott, a quadriplegic since dislocating his neck while playing rugby 19 years ago, said the possibility of the treatment was "huge" and gave hope to people with spinal cord injuries. "If nothing happens, at least you had a go ... you don't want to die wondering."

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Monday, October 27, 2008

Researchers Developing Therapy to Treat Paralysis

A team of researchers at Case Western Reserve University in Cleveland, Ohio are developing a new therapy that will help paralysis victims regain control of their muscles.

Functional Electrical Stimulation uses electric currents to stimulate muscles that no longer receive messages from the brain.

"When someone has a spinal cord injury, it's like they cut an electrical wire," Brian Heidenreich, associate professor of psychology, said. "The neurons that control muscles in the spinal cord are still there, but they don't get any messages from the brain."

Strokes may also damage or limit interaction between the brain and the muscles.

"Strokes wipe out the motor cortex, which controls motor movement in the body," Heidenreich said.

Organizations like the Food and Drug Administration, the State of Ohio and the National Institute of Health provide funding for FES research.

"The majority of the research programs at the Cleveland FES Center focus on spinal cord injury (SCI) and stroke," Mary Buckett, Cleveland FES researcher, said. "SCI programs at the FES Center vary and range from high level tetraplegia to incomplete paraplegia."

The actual treatment is an implanted prosthesis that restores communication between the brain and the muscles.

Researchers can also make the frontal lobe - the part of the brain that controls learning and thought - perform the tasks of the motor cortex with an FES device.

"It is possible to get brain regions to take over functions that weren't theirs originally," Heidenreich said.

Other FES programs focus on illnesses like Multiple Sclerosis and Osteoporosis. The programs are located in countries like Argentina, Canada, Australia, Poland, Japan and Italy.

A majority of the volunteers at the Cleveland center, Buckett said, have already sought traditional therapies. For them, FES treatment is seen as an additional opportunity to regain the ability to stand, apply make-up or write. In MS patients, FES therapy can reduce hand tremors by 50 percent.

The therapy may also restore basic bladder, breathing and hearing functions and eliminate the occurrence of urinary tract infections, loss of bone density and muscular atrophy.

Buckett, a former architect, explained in an FES Center document that her implant allows her to live as she did before she became paralyzed.

"I am less dependent on ? people to take notes in class for me or manipulate books and papers on my shelves and desk," she said.

"It has been amazing to witness individuals regaining function and independence," Buckett said. "To see someone stand from their wheelchair with pride and confidence and shake hands whilebeing introduced is a wonderful thing."

FES therapy still needs to go through additional testing, research, technological advances and FDA approval before researchers submit it for widespread use.

"This study is clearly a step toward making a device _that allows movement by people with paralysis, but it's one in a series that may achieve that goal," Heidenreich said.

By: Joanna Pelletier

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Sunday, July 20, 2008

Stem Cells Identified for Spinal-Cord Repair

A researcher at MIT?s Picower Institute for Learning and Memory has pinpointed stem cells within the spinal cord that, if persuaded to differentiate into more healing cells and fewer scarring cells following an injury, may lead to a new, non-surgical treatment for debilitating spinal-cord injuries.

The work, reported in the July issue of the journal PLoS (Public Library of Science) Biology, is by Konstantinos Meletis, a postdoctoral fellow at the Picower Institute, and colleagues at the Karolinska Institute in Sweden. Their results could lead to drugs that might restore some degree of mobility to the 30,000 people worldwide afflicted each year with spinal-cord injuries.

In a developing embryo, stem cells differentiate into all the specialized tissues of the body. In adults, stem cells act as a repair system, replenishing specialized cells, but also maintaining the normal turnover of regenerative organs such as blood, skin or intestinal tissues.

The tiny number of stem cells in the adult spinal cord proliferate slowly or rarely, and fail to promote regeneration on their own. But recent experiments show that these same cells, grown in the lab and returned to the injury site, can restore some function in paralyzed rodents and primates.

The researchers at MIT and the Karolinska Institute found that neural stem cells in the adult spinal cord are limited to a layer of cube- or column-shaped, cilia-covered cells called ependymal cells. These cells make up the thin membrane lining the inner-brain ventricles and the connecting central column of the spinal cord.

?We have been able to genetically mark this neural stem cell population and then follow their behavior,? Meletis said. ?We find that these cells proliferate upon spinal cord injury, migrate toward the injury site and differentiate over several months.?

The study uncovers the molecular mechanism underlying the tantalizing results of the rodent and primate and goes one step further: By identifying for the first time where this subpopulation of cells is found, they pave a path toward manipulating them with drugs to boost their inborn ability to repair damaged nerve cells.

?The ependymal cells? ability to turn into several different cell types upon injury makes them very interesting from an intervention aspect: Imagine if we could regulate the behavior of this stem cell population to repair damaged nerve cells,? Meletis said.

Upon injury, ependymal cells proliferate and migrate to the injured area, producing a mass of scar-forming cells, plus fewer cells called oligodendrocytes. The oligodendrocytes restore the myelin, or coating, on nerve cells? long, slender, electrical impulse-carrying projections called axons. Myelin is like the layer of plastic insulation on an electrical wire; without it, nerve cells don?t function properly.

?The limited functional recovery typically associated with central nervous system injuries is in part due to the failure of severed axons to regrow and reconnect with their target cells in the peripheral nervous system that extends to our arms, hands, legs and feet,? Meletis said. ?The function of axons that remain intact after injury in humans is often compromised without insulating sheaths of myelin.?

If scientists could genetically manipulate ependymal cells to produce more myelin and less scar tissue after a spinal cord injury, they could potentially avoid or reverse many of the debilitating effects of this type of injury, the researchers said.

Provided by MIT

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Thursday, July 17, 2008

Allen Institute Releases Spinal Cord Map

Spinal cord injuries have long baffled doctors. Now the Allen Institute for Brain Science is doing for spinal research what they did for brain science - providing the first comprehensive road map of a mouse's spine.

"It's a groundbreaking project that tells us where each gene in the genome is turned on in cells in the spinal cord," Dr. Allan Jones, Allen Institute's Chief Scientific Officer, said in a news conference Thursday. "This is very important because the genes ultimately contribute to the specific biochemistry of a particular cell."

Jones says because mice share many of the same genes with humans, the implications are far-reaching.

"Researchers working on things like spinal muscular atrophy, degenerative disease like MS and Lou Gerhig's disease or ALS , also people who suffer from spinal cord injuries," he said.

The first 2,000 genes are available online now, with the full map of 20,000 genes to be completed by the end of the year. All the information is free to scientists and the public.

"It's sort of a virtual microscope that scientists can come and zoom in," said Jones. "It's like having the microscope slide right there in front of them."

"The comprehensive map of the genes of the spinal cord will be an incredible resource for scientists and researchers studying how the spinal cord is altered in disease or an injury, and more importantly it's going to give hope to really millions of Americans who suffer from spinal cord diseases and disorders," Sen. Patty Murray said at the news conference.

Said each day, 1,000 scientists have been accessing the Allen Brain Atlas Project, which went live in December of 2004 and was completed in 2006.

"Researchers have been using this to support all aspects of brain research," said Jones. "Just some examples: Alzheimer's, autism, bipolar, Down syndrome, Fragile X mental retardation, epilepsy, alcoholism, obesity, Parkinson's disease, sleep, hearing, memory, and more."

In December, Marine Corporal Jerold Mason was paralyzed in a car crash. These days he's grateful for the small things, like being able to listen to his I-Pod.

"It like takes you away from the stress. I will always use music to do that," he said.

Mason can now control his I-Pod with a straw. This one small step is inspiring him.

"Allows me to think of times when I did have the use of my arms, my legs and you know it makes me want to push harder," he said.

Thanks to the spinal cord map, researchers will be able to push harder, as well.

"It's all undiscovered new stuff. So they're a bit like a kid in a candy store in terms of the new data in the excitement of looking at it," said Jones.

Microsoft co-founder Paul Allen started the mapping project with $100 million in seed money. It's now grown to include other private, as well as public, funding.

Story By JEAN ENERSEN

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Friday, April 18, 2008

New Discovery May Aid Treatment of Spinal Cord Injuries

A discovery by researchers at University of Minnesota may provide new insights into how the spinal cord controls walking, and this may pave the way for developing treatments for diseases of the central nervous like Parkinson?s disease and spinal cord injuries.

Led by Joshua Puhl, Ph.D., and Karen Mesce, Ph.D., in the Departments of Entomology and Neuroscience, the study has found a possibility that the human nervous system, within each segment or region of spinal cord, may have its own unit burst generator to control rhythmic movements such as walking.

The researchers chose to study a simpler model of locomotion in the medicinal leech, and this uncovered the residing spots of these unit burst generators and it also showed that each nerve cord segment has a complete generator.

It was discovered that a neuron triggers to set off a chain reaction that gives rise to rhythmic movement and the moment those circuits are turned on, the body essentially goes on autopilot.

The researchers mainly focused on the segmented leech for study as they have fewer and larger neurons, making them easier to study.

For most of us, we can chew gum and walk at the same time. We do not have to remind ourselves to place the right leg out first, bring it back and do the same for the other leg. So how does the nervous system control rhythmic behaviors like walking or crawling, said Mesce.

The study also discovered that dopamine, a common human hormone, can turn each of these complete generator units on.

Because dopamine affects movement in many different animals, including humans, our studies may help to identify treatments for Parkinsons patients and those with spinal cord injury, said Mesce.

The study was published online in the Journal of Neuroscience.

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Tuesday, January 08, 2008

Scientists Able to Get Mice with Spinal Injuries to Walk

Scientists conducting research have been able to gain fresh insights into how partial mobility is possible despite spinal injuries. The research, conducted on mice with spinal injuries could provide a totally different approach to restoring mobility, even if it is partial, in patients who have suffered similar injuries.

Scientists conducting research have been able to gain fresh insights into how partial mobility is possible despite spinal injuries. The research, conducted on mice with spinal injuries could provide a totally different approach to restoring mobility, even if it is partial, in patients who have suffered similar injuries.

In the study, mice were inflicted with spinal injuries in the laboratory. Over a period of two to two and a half months (eight to 10 weeks), the mice were able to walk again, though not as fluently as they used to before the injuries.

The study involving the mice highlighted the fact that after a spinal cord injury, the brain and the spinal cord had the ability to reorganize their functioning and re-establish the communication network needed at the level of the cell to execute the task of walking.

Scientists said after the mice suffered from the partial spinal cord injuries, the neural networks in the brain and the spinal cord reorganized themselves. The reorganization was done in such a way that though the long and continuous neural highways transmitting impulses between the brain and the center for walking located in the lower regions of the spinal cord were broken, the mice were still able to walk.

Researchers are quite excited about the new findings. As Dr. Michael Sofroniew, neurobiology professor at the University of California Los Angeles? David Geffen School of Medicine and lead researcher put it, ?This is not the end of a story. This is the beginning of a story.?

Dr. Sofroniew said the research team was able to identify a mechanism that aided the functionality recovery from partial spinal cord injuries that no one knew about earlier. He said there was still work to be done, and that scientists now could focus on understanding this mechanism better so they would be able to know how to make better use of it.

Dr. Sofroniew said they could achieve this by undertaking the right approach to rehabilitation therapy and also determining how to stimulate this alternative network. The research is almost revolutionary as so long, scientists were of the opinion that the only way to get a person with a spinal cord injury to walk again was to have the long neural highways grow back and connect the brain to the spinal cord base.

The spinal cord basically passes through the neck of a person, down the back. It transmits messages between the brain and the different parts of the body. Any serious injury to the spinal cord, as in a car accident, can sever the long neural highways, causing the patient to be paralyzed. So far, scientists had not been able to cure paralysis of this kind.

The new research shows that when the damage to the spinal cord causes the neural highways to break down and stop messages transmitted from the brain from reaching the designated parts, it was possible for the messages to find alternative ways to reach the destination.

For instance, if the instruction from the brain was to move the leg, as in the case of walking, it would not go over the neural highway; instead, it would travel over an alternate network consisting of a number of shorter connections to ensure the message from the brain reached the legs.

Dr. Sofroniew said the situation was somewhat akin to a traffic situation. If there is a jam on the freeway, one could get on to interconnected and shorter side roads to circumvent the jam and reach the destination. That was how it was in the case of message transmission in the laboratory mice, he said.

During the research, the team shut down half the neural fibers on either side of the spinal cord without disturbing the center. The center has a series of interconnected neural passages to send and receive information between the top and the bottom of the spinal cord.

In the next step, the researchers blocked the short passages as well, and the paralysis came back, confirming the messages had earlier gone to their destination over these shorter networks, which had been earlier left open.

The next step, researchers say, is to find out how to enable the spinal cord nerve cells to develop and grow around a specific injury site so the brain can work with these cells instead and ensure there is no paralysis.

The team of scientists conducting the research has published its work in the journal Nature Medicine.

by Daisy Sarma

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Wednesday, November 07, 2007

New Clinical Trials Could Open "Golden Era" In Spinal Cord Injury

New experimental therapies are being -- or soon may be -- tested in clinical trials that could open the doors to a "golden era" for research to improve the treatments of people with spinal cord injuries, brain injuries, stroke, and other severe movement disorders, scientists say.

"The studies highlighted here reflect decades of basic science research that have led to some measure of understanding the events taking place in traumatic neural injury and disease, and how these events can be modulated to improve function," says Aileen Anderson, PhD, of the University of California, Irvine.

"As a result of this work, we have the exciting opportunity to begin testing these pathways in the clinical setting in an attempt to minimize the progression of damage and, in some cases, perhaps repair it," says Anderson.

The new therapies include an experimental, custom-made antibody to NOGO-A, one of several inhibitory proteins for nerve fiber growth that are produced naturally in the human spinal cord and brain. It soon will be evaluated as a therapy for patients who are newly paralyzed from spinal cord injury.

This Phase I clinical trial, conducted by the European Network of Spinal Cord Injury Centers, follows extensive laboratory research on NOGO-A, as well as animal tests of the experimental monoclonal antibody's effectiveness in neutralizing the inhibitory protein.

NOGO-A is one of several proteins whose existence in the adult body helps to explain our limited ability to grow new brain and spinal cord tissue in response to injury or disease, says Martin Schwab, PhD, of the Brain Research Institute at the University of Zurich in Switzerland. These inhibitory proteins, which are silent during embryonic and fetal development and even during the first few months of an infant's life, vigorously limit the inherent ability of adult brain and spinal cord neurons to regrow fibers that have been cut by injury.

"As a result, neurons as well as their axons retain a low growth potential following brain trauma or spinal cord injury," Schwab says. Axons transmit from neurons the electrical impulses that underlie our ability to move our arms and legs.

To restore fiber-growing ability to the brain and spinal cord, Schwab first prevented NOGO-A from fulfilling its function as an inhibitor of fiber growth and regeneration in laboratory animals. He showed that the anti-NOGO-A antibody allowed fiber tracts of the rats' damaged spinal cords to regenerate partially, thereby restoring some motor function.

"Animals treated with such reagents showed molecular changes which strongly suggest that the growth machinery of the nerve cells is turned on, similar to the situation during development," Schwab says. Anatomical studies showed that the antibody treatment induced long-distance regeneration and the formation of new circuits.

"Nerve fiber tracts that were not directly affected by the injury also sprouted after treatment," Schwab says. These physical changes restored some of the animals' leg movement, a "remarkable behavioral recovery," he adds. "Many animals showed almost full recovery in sensory as well as motor tests." The untreated, or control, animals in the study remained severely impaired.

"The coming few years will show whether the step from bench to bedside can be successfully achieved in spinal cord injury and central nervous system trauma without the danger of serious side effects or complications," Schwab says.

In another presentation, Michael Fehlings, MD, PhD, of the Toronto Western Hospital and University of Toronto described several current or planned clinical trials for treating spinal cord injury. Immediate treatment may not only reverse the initial damage to the spinal cord but also may minimize secondary injury, potentially sparing the patient additional neurological problems, Fehlings says.

The prospective clinical study, titled STASCIS, which is evaluating the role and timing of early decompressive surgery in patients with cervical spinal cord injury, has to date enrolled more than 240 patients. The study, he says, is based on the premise that within hours of a spinal cord injury, a patient should be undergoing surgery that will reduce pressure on the cord in order to limit damage to it and surrounding tissues. Initial evaluations of the clinical trial data have indicated that immediate surgery is safe and feasible and, by reducing the pressure on a compressed spinal cord, may encourage the recovery of function.

In another clinical trial, scientists soon will determine whether the Food and Drug Administration-approved medication riluzole protects nerve cells and promotes functional recovery when it is administered after spinal cord injury. Riluzole, now used to treat people with amyotrophic lateral sclerosis (ALS), prevents neurons from releasing too much sodium. In lab animal studies, the drug was neuroprotective.

In other animal model studies, the drug CethrinŽ has been found to lessen post-traumatic neural cell death. To evaluate the safety of this recombinant protein drug and obtain preliminary efficacy data in human patients, Fehlings and colleagues at nine centers in the United States and Canada administered the agent topically to 37 patients with complete cervical and thoracic spinal cord injury. "The drug shows a high degree of safety and promising clinical neurological improvements after one year of follow-up," he says.

"While the results of a single arm, uncontrolled study need to be interpreted cautiously, this level of improvement exceeds rates of spontaneous neurological recovery," Fehlings says. A prospective, randomized placebo-controlled efficacy trial is planned for early 2008.

The Fehlings team has completed studies in lab rodents in which neural stem cells were transplanted following spinal cord injury. The stem cells, programmed to restore the myelin layer around spinal cord nerve fibers, promoted significant neurological recovery. This strategy shows considerable promise for translation into the clinic, Fehlings says.

If it continues beyond a critical time point, the medical practice of treating spinal cord-injured patients with immune suppressive drugs as soon after the injury as possible may hinder rather than promote recovery, according to studies by Michal Schwartz, PhD, of the Weizmann Institute of Science in Rehovot, Israel.

"For many decades, the detection of immune cells in the injured brain or spinal cord was interpreted to represent part of the pathological process that occurs following injury and prevents healing," Schwartz says. "This dogma was so well ingrained that the common practice in Western countries has been to treat patients who experienced spinal cord injury with immune suppressive drugs as early as possible following the injury."

However, Schwartz's laboratory showed that the immune system is required for protection, repair, and renewal of the brain and spinal cord following acute or chronic damage. But, she says, "to achieve beneficial results, immune-cell involvement in repair must be critically controlled in terms of the timing, nature, intensity, and duration of activation."

A beneficial immune response involves not only the activity of immune cells residing in the damaged tissue, but also the timely recruitment of immune cells from the blood. These blood-borne immune cells home to a precise location around the injured site, where they sense the tissue damage and secrete factors needed to induce repair.

"This timely recruitment of immune cells to the site of injury, and their well-controlled activation, is an essential stage in the multistep process of brain and spinal cord repair," Schwartz says. "Curtailing this process by suppressing, rather than modulating, the immune response deprives the tissue of its most powerful physiological repair mechanism."

Schwartz designed and tested several immune-based therapeutic approaches for promoting spinal cord repair. One was a vaccine containing a peptide derived from a protein that resides in the injured tissue and that can boost immune response by activating a particular population of immune cells, the T lymphocytes. T lymphocytes specifically recognize proteins that are associated with the injury.

Pairing the vaccine with an injection of neural stem cells resulted in a synergistic effect on recovery. "Surprisingly, however, the injected stem cells did not themselves give rise to new neurons but rather promoted the formation of new neurons from the tissue's resident stem cells," Schwartz says.

Scientists also have found in work with laboratory animals that when human stem cells are transplanted into the body, they form active synapses with the animal's own neurons for limb movement. After they were implanted, the human stem cells developed into neurons and made local connections with spinal cord motor neurons but they did not project to the animals' peripheral nerve and hind limb muscles, says Vassilis Koliatsos, MD, of Johns Hopkins University.

Koliatsos conducted this study with rodents affected by a genetic form of ALS, which is characterized by the progressive degeneration and death of motor neurons. "These findings demonstrate that grafted human neural stem cells become synaptically incorporated into the motor circuitry of ALS rats," Koliatsos says.

The exact role of these new synapses, which are specialized junctions through which neurons signal each other, is not yet defined. Koliatsos says that they may serve to communicate physiological signals pertaining to limb movement or, more likely, to transfer nourishing chemicals from neural stem cells to the degenerating or vulnerable motor neurons of the host ALS animal.

The transplanted human stem cells produced an abundance of two key nourishing chemicals for motor neurons: glial cell-derived neurotrophic factor and brain-derived neurotrophic factor (BDNF), which, Koliatsos says, "may be the main factor behind the therapeutic effect of neural stem cell grafts."

In the latest study, the implanted human neural stem cells, obtained from a 2-month-old human fetal spinal cord, were transplanted into the spinal cord of ALS rats when they were 9 weeks old.

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Friday, September 07, 2007

Skin Stem Cells Used to Mend Spines of Rats

Toronto research shows injured subjects walking better after injections

A Toronto-led team of researchers has found a way to use stem cells derived from skin to treat spinal cord injuries in rats.

The finding lends promise to the idea that stem cells could one day be used to heal spinal cord injuries in humans, helping thousands to walk again.

Injured rats injected with skin-derived stem cells regained mobility and had better walking co-ordination, according to the study published yesterday in the Journal of Neuroscience. The skin-derived stem cells, injected directly into the injured rats' spinal cords, were able to survive in their new location and set off a flurry of activity, helping to heal the cavity in the cord.

Freda Miller, a senior scientist at The Hospital for Sick Children and lead author of the study, said skin-derived stem cells have some advantages over other stem cell types. Scientists who use skin to generate stem cells do not need to use embryos, for example, and skin-derived stem cells can potentially be harvested from patients themselves, she said.

"You can imagine a scenario for people with spinal cord injuries, that maybe, just maybe, we could take a piece of their skin, grow the cells up and transplant them (the patient) with their own cells," she said. "You wouldn't have to give them immunosuppressive drugs. That's a tremendous clinical advantage if it comes true."

Miller and her colleagues from The Hospital for Sick Children and the University of British Columbia have been exploring the possibilities of using skin to derive stem cells since 2001.

Over the course of their research, the team found that skin-derived stem cells share characteristics with embryonic neural stem cells, which generate the nervous system. They also showed skin-derived stem cells can produce Schwann cells, a cell type that creates a good growth environment to repair injured central nervous system axons ? the long nerve cell fibres that conduct electrical impulses between nerves ? and that these Schwann cells put down myelin along the injured spinal cord. Like the insulation around an electrical cord, myelin wraps around nerves, creating a sheath that helps quickly conduct nerve impulses.

Miller said the next step was to see whether transplanting the Schwann cells directly into spinal cords would help treat injured rats.

To test their hypothesis, Miller and her team generated stem cells from the skin of rats and mice and forced them to differentiate into Schwann cells, which were then transplanted into the rats. After 12 weeks, the rats were able to walk better, with more co-ordination.

Miller said the cells thrived within the injured spinal cord. Before treatment, the injured rats had a cavity in their spinal cord, a result of their injury. But after treatment, Miller said the Schwann cells had created a bridge that spanned the cavity, and helped nerves grow through the bridge.

The next step is to see whether stem cells derived from human skin can produce similar results.

"We are highly encouraged," said Miller.

Story by: Megan Ogilvie

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Thursday, May 10, 2007

Stem Cells Closer to Trials

Despite the limitations on federal funding for embryonic stem cell research, two companies recently said they are close to entering clinical trials with the versatile cells.

Geron plans to file an investigational new drug application with the Food and Drug Administration by the end of the year for using cells derived from embryonic stem cells for treating spinal injuries.

Advanced Cell Technology, which previously said it planned to file an IND this year for using stem cell-derived therapies for treating macular degeneration, announced this week it has developed a technique to generate a type of progenitor cell that could move into the clinic in 2008 for treating a variety of ills.

Robert Lanza, Advanced Cell's vice president of medical and scientific affairs, told United Press International that the cells -- called hemangioblasts that his group derived from human embryonic stem cells -- have proven their ability to repair vascular damage in the eyes and limbs of animals. This indicates the cells could prove beneficial for treating heart attacks, reversing vascular damage that now requires limbs to be amputated, and other conditions.

"We're planning to file with the FDA next year to use them in patients," Lanza said.

Advanced Cell's technique is described in the online issue of Nature Methods. Although it's still in the early days, he said the hemangioblasts also could be used to create immune tolerance so the body does not reject the cells as foreign.

"This would allow us to transplant any type of replacement cell or organ generated from a specific stem cell line without rejection," Lanza said. "It would make therapeutic cloning unnecessary and obviate the need for millions of human eggs."

Lanza said animal studies his firm currently has in progress indicate the hemangioblasts could help repair lung damage and generate enough red blood cells for transfusion.

Other potential indications include treating strokes, microvascular complications of diabetes and atherosclerosis.

Advanced Cell, whose California facility could be a benefactor of the $3 billion stem cell program in that state, also may reap the rewards on the other coast where its Worcester, Mass.-based facility is located. Massachusetts Gov. Deval Patrick Tuesday announced his proposal to make $1.25 billion available for funding stem cell and other research in the state over 10 years.

Under the terms of the proposal, the majority of the funding would come from the state, while $250 million would come from private businesses.

UPI could not reach Geron CEO Thomas Okarma by press time Wednesday, but the company has said it anticipate filing an IND for GRNOPC1 for treating spinal-cord injuries around the December timeframe.

GRNOPC1, which consists of oligodendroglial progenitor cells derived from human embryonic stem cells, has been shown to stimulate the regeneration of damaged neurons in pre-clinical studies.

Lazard analyst Joel Sendek, who rates the stock a "hold," notes Geron's products, since they are cellular-based therapies, carry substantially more risk than conventional drugs or protein therapies.

Despite that uncertainty, the company's GRNOPC1 may have an advantage over stem cell-based therapies aimed at other indications.

"We believe the bar for signs of efficacy is low, given that (spinal-cord injury) patients have no other options for restoration of function," Sendek stated in a research report.

However, the FDA is concerned about the potential for stem cell-derived therapies to cause tumors in humans, so Geron will have to overcome that barrier with the agency, Sendek said.

He anticipates the company will file the IND for GRNOPC1 in the fourth quarter and start a phase 1/2 program in the first half of 2008.

The phase 1/2a trial, which Sendek anticipates will take two years to complete, will initially involve 75 patients with spinal-cord injuries. GRNOPC1 cells will be injected into the spinal-cord lesion and the patients will also be given an immunosuppressant drug to prevent rejection of the cells.

Mark Monane, an analyst with Needham, thinks the IND filing for GRNOPC1 and advancement of its other pipeline candidates will be significant events for Geron, but added they probably won't add much value to the stock.

"Given the current technology value of $288 million, we believe that the market has already priced in the expected pipeline progression," Monane stated in a research report. "Going forward, we believe that the stock will perform in line with the overall market until (generation of) further clinical efficacy data from Geron's multiple product candidates."

The company's other candidates include GRN163L for chronic lymphocytic leukemia. A potential catalyst for the stock is Geron's slated presentation of early phase 1/2 data for GRN163L at the Pan Pacific Lymphoma Conference in June.

By STEVE MITCHELL
UPI Senior Medical Correspondent

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Tuesday, April 24, 2007

Simple Injection Shows Promise for Treating Paralysis

Paralyzed lab rodents with spinal cord injuries apparently regained some ability to walk six weeks after a simple injection of biodegradable soap-like molecules that helped nerves regenerate.

The research could have implications for humans with similar injuries.

"It will take a long time, but we want to offer at least some improvement, to improve quality of life for people with these injuries," materials scientist Samuel Stupp at Northwestern University in Evanston, Ill., told LiveScience. "Anything would be considered a breakthrough, because there's nothing right now."

The soap-like molecules contain a small piece of laminin, a natural protein important in brain development. After these molecules are injected into the body, they react with chemicals there, assembling themselves instantly into scaffolds of super-thin fibers just six billionths of a meter wide, roughly a hundredth a wavelength of orange light. They biodegrade after roughly eight weeks.

The scientists experimented with their molecules on dozens of mice and rats that experienced spinal cord injuries that paralyzed their hind legs, "the kind of very hard blow people might experience after falling off skiing slopes or getting in car accidents," Stupp said. His colleague, neurologist John Kessler, became active in this work after Kessler's daughter was paralyzed in a skiing accident.

After six weeks, damaged nerves regenerated enough for the paralyzed legs of the rodents to regain some ability to walk.

"There's a special scale to monitor how much function they regained, ranging from 0 to 21," Stupp explained. "At 21, function is perfect. At 6 or 7, limbs are just paralyzed, and the mice were just dragging them along. If you go to 9 to 12, the animal can now actually move the limbs. Not perfectly?awkwardly?but they move. So two or three points on that scale makes a huge difference."

"We've been able to go from a 7 to a 9 in the mouse, and in the rat, the highest was 12," he said. The findings are to be presented today at a meeting of the Project on Emerging Nanotechnologies in Washington, D.C.

The researchers are currently in talks with the FDA regarding their work and hope to start phase I clinical trials (for toxicity and safety testing) in humans two years from now, Stupp said. The idea he and his colleagues have for these molecules is to administer them within a day or so after spinal cord injuries, before scar tissue begins to form that can suppress healing. Past experiments have shown these molecules can actually turn neural stem cells (which might otherwise become scar cells) into neurons instead.

"Recovering every function a person had before an injury will probably be very hard," Stupp cautioned. "Even if people couldn't walk, if they could recover bladder function, that'd be a good thing. It's the first thing I'd want to recover."

The researchers now are developing versions of these soap-like molecules that could help with regeneration when it comes to other maladies such as Parkinson's disease, stroke, heart attacks, bone trauma or diabetes.

By Charles Q. Choi

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