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.

Labels: , , , ,

Read the Full Post!
 

Friday, November 21, 2008

Nanotechnology for Spinal Cord Injury

A cure for spinal injuries that leave people paralyzed, currently incurable, is being developed by Researchers at Northwestern University in Chicago. They are looking into using new nanotechnology that could enable them to completely heal cut and severed spinal cords allowing the previously paralyzed to walk again.

Spinal cord injury often leads to permanent paralysis and loss of sensation below the site of the injury due to damaged nerve fibers which can?t regenerate. These nerve fibers (axons) have the capacity to grow but don?t because they are blocked by scar tissue that have developed around the injury. Northwestern University researchers have shown that a new nano-engineered gel inhibits the formation of scar tissue at the injury site and enables the severed spinal cord fibers to regenerate and grow.

The gel is injected as a liquid into the spinal cord and self -assembles into a scaffold that supports the new nerve fibers as they grow up and down the spinal cord, penetrating the site of the injury. When the gel was injected into mice with a spinal cord injury, after six weeks the animals had a greatly enhanced ability to use their hind legs and walk.

However it was stressed that the results were preliminary and there is no magic bullet and it may not necessarily work on humans, but it helps a new technology to develop treatments for spinal injuries.

Labels: , , , , , , , , ,

Read the Full Post!
 

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.

Labels: , , , ,

Read the Full Post!
 

Tuesday, April 08, 2008

Nanotechnology May Help Reconnect Nerves

U.S. researchers say they have created a nano-engineered gel that can enable severed spinal cord fibers to regenerate and grow.

Mice paralysed by spinal injuries have been able to walk again thanks to a treatment developed by scientists in the US. The therapy uses proteins that self-assemble into nano-fibers at the site of the injury, encouraging nerves to regrow.

Spinal cord injuries often lead to permanent paralysis and loss of sensation because the damaged nerve fibers can't regenerate, Northwestern University scientists said. Although nerve fibers or axons have the capacity to re-grow, they don't because they're blocked by scar tissue that develops around the injury.

The nanogel developed at the university's Feinberg School of Medicine inhibits formation of scar tissue and enables the severed spinal cord fibers to regenerate and grow, the scientists said.

The gel is injected as a liquid into the spinal cord and self-assembles into a scaffold that supports new nerve fibers. When the gel was injected into mice with a spinal cord injury, after six weeks the animals had a greatly enhanced ability to use their hind legs and walk.

"It's important to understand that something that works in mice will not necessarily work in human beings," said study leader Dr. John Kessler, who noted that if the gel is eventually approved for humans, a clinical trial could begin within several years.

The research is reported in the Journal of Neuroscience.

Labels: , , , ,

Read the Full Post!
 

Sunday, February 17, 2008

Spinal Cord Injury Regeneration Hope

Scientists believe they are close to a significant breakthrough in the treatment of spinal injuries.

The University of Cambridge team is developing a treatment which could potentially allow damaged nerve fibers to regenerate within the spinal cord.

It may also encourage the remaining undamaged nerve fibers to work more effectively.

Spinal injuries are difficult to treat because the body cannot repair damage to the brain or spinal cord.

Although it is possible for nerves to regenerate, they are blocked by the scar tissue that forms at the site of the spinal injury.

Scientists believe they are close to a significant breakthrough in the treatment of spinal injuries.

The Cambridge team has identified a bacteria enzyme called chondroitinase which is capable of digesting molecules within scar tissue to allow some nerve fibers to regrow.

The enzyme also promotes nerve plasticity, which potentially means that remaining undamaged nerve fibers have an increased likelihood of making new connections that could bypass the area of damage.

Boosts rehabilitation

In preliminary tests, the researchers have shown that combining chondroitinase with rehabilitation produces better results than using either technique alone.

However, trials have yet to begin in patients.

Lead researcher Professor James Fawcett said: "It is rare to find that a spinal cord is completely severed, generally there are still some nerve fibers that are undamaged.

"Chondroitinase offers us hope in two ways; firstly it allows some nerve fibers to regenerate and secondly it enables other nerves to take on the role of those fibers that cannot be repaired.

"Along with rehabilitation we are very hopeful that at last we may be able to offer paralyzed patients a treatment to improve their condition."

'Ground-breaking'

Dr Yolande Harley, of the charity Action Medical Research which funded the work, said: "This is incredibly exciting, ground-breaking work, which will give new hope to people with recent spinal injuries."

Paul Smith, of the Spinal Injuries Association, said medical advances meant that spinal injuries had ceased to be the terminal conditions that they often once were, but they still had a huge impact on quality of life.

However, he warned against raising expectation before the treatment was fully tested on patients.

He said: "What often happens in a clinical setting is that you don't get to see the results you would have liked."

In the UK there are more than 40,000 people suffering from injuries to their spine, which can take the form of anything from loss of sensation to full paralysis.

The average age at the time of injury is just 19.

Labels: , , , , , , ,

Read the Full Post!
 

Thursday, February 07, 2008

Could a Spinal "Bypass" Reverse Paralysis?

A breakthrough in spinal surgery yesterday offered hope to victims of paralysis.

The technique, which has been tested on rats, involves bypassing damaged tissue in the spine.

This allows signals to travel across injured areas, New Scientist reports.

Dr John Martin and his colleagues at Columbia University in New York have so far tested the procedure only on rodents. They selected a motor nerve branching from the healthy cord above the injury and cut it away from the abdominal muscle to which it is normally attached.

They then stretched the free end across the injured section of spinal cord and used a protein "glue" to fix it.

Two weeks later the team found that the graft had sprouted new extensions which had begun to form connections - or synapses - with the motor nerves in the isolated lower spine.

Zapping the spinal cord above the injury made the lower limbs of the rats twitch - showing motor signals had started once again to pass along the entire length of the spine.

The researchers say removing the nerve from the abdominal muscle did not appear to cause any major side effects and suggest this is because nearby nerves pick up the slack.

Fellow neuroscientist Dr Reggie Edgerton, of California University, said the approach had considerable clinical potential but added that it was too early to tell whether it would work in humans.

Dr Marie Filbin of the City University of New York cautioned that it may not be possible to "reprogramme" a nerve that normally connects to an abdominal muscle to transmit the sophisticated signals needed to produce fine, controlled movements.

But Dr Martin, who presented his study at the New York State Spinal Cord Injury Research Program Symposium, said: "What we want to do is plug in new connections to bypass the damaged region."

He believes that - with a little surgical assistance - spinal cord nerves above an injury could be capable of making such connections with nerves lower down the spine.

He said: "We know the nerves can make new connections to muscle so we asked whether it's possible for them to also connect with spinal cord neurons isolated through injury."

Labels: , , , , , ,

Read the Full Post!
 

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.

Labels: , , , , , , ,

Read the Full Post!
 

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

Labels: , , , , ,

Read the Full Post!