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 21, 2007

Drug Can Help Patients Heal From Spinal Cord Injuries

According to the Spinal Cord Injury Information Network, there are about 11,000 new spinal cord injuries each year. Car accidents have been responsible for nearly 50 percent of spinal cord injuries since 2000, and falls have been the second most common cause of spinal cord injuries. Currently, about 253,000 Americans are living with a spinal cord injury.

Dr. Michael Fehlings from Toronto Western Hospital is studying a new drug to treat spinal cord injuries soon after they happen. The drug, called Cethrin, is applied during surgery to the injury site in a fibrin glue type of material. Cethrin is a recombinant protein that is made through artificial DNA technology. The protein inhibits Rho, a key pathway that triggers cell death and increases damage after a spinal cord injury.

"You apply [Cethrin] directly to the damaged spinal cord and then the medication penetrates the damaged spinal cord," Fehlings said.

Cethrin is still under study, but early results look promising. Results from a one-year study of the drug in 37 patients were presented in April, 2007 at the annual meeting of the American Association of Neurological Surgeons in Washington, D.C. All patients in the study had "A" grade injuries, which are the most serious. Injuries are graded from A to E, with A being the most serious and E being the least serious.

Patients received Cethrin an average of 53 hours after their injury occurred. After six months, 28 percent of patients improved by one or more grades. Five patients improved to a "C" grade, and two improved to a "D" grade.Typically, there is some recovery that occurs after an injury, but the rates of recovery are quite low, in the range of 5 percent to 10 percent.

"In this trial, fully a third of patients showed significant recovery, and almost 20 percent of the patients showed a major degree of recovery. In my own clinical experience, this type of recovery is very unusual," Fehlings said.

Fehlings says the drug is not a cure for spinal cord injuries, but it could have a major impact on patients' lives.

"They might be able to now grip a jar or to drink, or they might be able to transfer themselves, whereas before they might not have had trunk control. In some patients, it might even mean that they could recover the ability to walk," he said.

At least five institutions in the United States and three in Canada are studying Cethrin's role in spinal cord injuries.

By: Ivanhoe Broadcast News

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Tuesday, May 01, 2007

Doctors Try New Injection To Fight Paralysis

There are currently no effective therapies for spinal cord injuries. But a protein injection may help some patients walk again.

Two years ago, Michelle Robinson was on her way home from work when she was hit by a car.

"All I remember is hearing a loud screeching noise and I remember going, flying up in the air," Michelle said.

The accident left the 42-year-old mother paralyzed. Now she hopes an experimental drug will put her back on her feet.

"It appears that this actually does improve their prognosis," said James Harrop, a neurosurgeon.

Harrop is testing the novel drug called Cethrin to treat spinal cord injuries.

"It's a paste or a jelly that you sort of just spread onto the spinal cord with a little applicator, like a syringe," he said.

Doctors apply the protein during standard decompression surgery to stabilize the spine. The idea is to stop nerve cell death that includes days to weeks after the injury occurs.

"Inside the cell, there?s a nucleus which is controlling sort of this, the auto-regulator of the cell and what it?s doing is it?s telling the cell we don?t want you to function anymore," Harrop said.
Cethrin is designed to interfere with that message by seeping through the spinal cord membrane to cells at the injury site.

"It goes into the cell and it says 'wait a minute'. I don't want you guys going down that path anyways, I want you to stop and I want you to start repairing the cell," Harrop said.

Early trials show the protein therapy is safe. And the results are promising. Michelle says she is both excited and hopeful the new therapy will work for her.

"I say those words because Dr. Harrop told me that he was very hopeful that, you know, maybe one day I would be able to walk again, so I'm very hopeful also."

Doctors caution that Cethrin, also called BA210, is not a magic bullet. But in the study, 31 percent of patients regained some function after being injected with the drug. The study is still enrolling patients. About 253,000 Americans are living with a spinal cord injury. Roughly 11,000 new cases occur every year.

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Wednesday, April 18, 2007

Drug Shows Promise in Spinal Cord Injury Treatment

A drug called Cethrin shows promise in treating people with spinal cord injury (SCI), according to a study by American and Canadian researchers.

Cethrin inhibits Rho, a signaling master switch that, when activated, triggers cell death and increases damage after SCI. Tests in animals with SCI have found that Cethrin inhibits cell death and promotes neural regeneration.

This one-year study looked at the use of Cethrin (a recombinant protein) formulated with a fibrin sealant in 37 patients who had just suffered an SCI that left them with no sensory or motor function below the area of the injury.

All the patients had an "A" grade injury as ranked by the American Spinal Injury Association (ASIA). Grades of injury go from A through E. An "A" is the most serious while "E" is normal.

After the patients had surgical decompression/reconstruction, the researchers started treatment with Cethrin, an average of 53 hours after the injury occurred. The patients received increasing doses of the drug (0.3, 1.0, 3.0 and 6 milligrams) administered extradurally to the injured spinal cord. The patients were assessed at various points over a year.

The study found that at six weeks, 30.6 percent of the patients improved by one or ASIA grades of injury. At six months, 28 percent of patients improved by one or more ASIA grades. Five patients improved to "C" and two improved to "D." One patient died from acute respiratory distress syndrome.

The study, which was funded by BioAxone Therapeutique of Montreal and Boston Life Sciences Inc., was presented Monday at the annual meeting of the American Association of Neurological Surgeons, in Washington, D.C. The findings from this Phase I/II study warrant moving on to a prospective randomized trial of Cethrin, the researchers said.

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