Saturday, November 27, 2004

Stem cell therapy helps patient walk again, South Korea

A team of Korean researchers claimed Thursday they had performed a miracle by enabling a patient, who could not even stand up for the last 19 years, to walk with stem cell therapy.

During a press conference, the scientists said they had last month transplanted multi-potent stem cells from umbilical cord blood to the 37-year-old female patient suffering from a spinal cord injury and she can now walk on her own.

The team was co-headed by Chosun University professor Song Chang-hun, Seoul National University professor Kang Kyung-sun and Han Hoon, Ph.D, from the Seoul Cord Blood Bank (SCB).

"The stem cell transplantation was performed on Oct. 12 this year and in just three weeks she started to walk with the help of a walker," Song said.

The patient's lower limbs were paralyzed after an accident in 1985 damaged her lower back and hips. Afterward she spent her life in bed or in a wheelchair.

For the unprecedented clinical test, the scientists isolated stem cells from umbilical cord blood and then injected them into the damaged part of the spinal cord.

The sensory and motor nerves of the patient started to improve 15 days after the operation and she could move her hips. After 25 days, her feet responded to stimulation.

Earlier in October 2003, Song's team also staged a clinical test with stem cells originating from umbilical cord blood by injecting them into another patient's spine.

"Back then we injected stem cells into spinal fluid and failed to get a good result. This time around, we directly targeted the spine and the method made a difference," Song said.
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Israeli-made device helps restore use of paralyzed hands

Stroke sufferers or victims of a spinal cord injury often lose partial use of their hands. As a result, they can spend agonizing months in rehabilitation, attempting to perform simple tasks like lifting and carrying objects, drawing, writing and personal grooming.

Now a powerful device developed in Israel which can restore the use of a partially paralyzed hand due to neurological damage is available to the millions of American who have suffered a stroke and are going through the rehab process.

The NESS-H200 was developed by an Israeli firm, Neuromuscular Electrical Stimulation Systems Ltd. (NESS), to treat impairment of the hand and shoulder from stroke or spinal cord injury and to relieve complications such as swelling and the painful contraction or atrophy of muscles.

A brace-like device fits snugly over the forearm and hand, with built-in electrodes touching key muscles. It's connected to a portable unit easily operated by the patient that may be set in different modes, to exercise the hand by shocking the muscles to open and close the fingers and to help the hand grasp and release objects.

"It improves the quality of daily living," said Roger Nathan, the founder of NESS Ltd. NESS is an acronym for Neuromuscular Electric Stimulation Systems. And in Hebrew, 'ness' means miracle, which is the way many people feel about their enhanced manual abilities gained by using the compact device.

An associate professor of biomedical engineering in Ben-Gurion University's department of mechanical engineering, Nathan's research in electrical stimulation of the neuromuscular tract led to the development of the device.

"It works through the nerve/muscle junction, the connecting point," he told ISRAEL21c. "Neuromuscular stimulation enhances physiological and metabolic activity in the peripheral nerves, muscles, connective tissue, and their blood supply."

"Over half of the people who suffer a stroke have paralysis of the hand," said Nathan. Eighty percent suffer secondary complications after a stroke, including a pain syndrome in the hand and shoulder, a 'psychological amputation' because of learned non-use, spasticity, poor blood circulation, tissue shortening and further degeneration of the limb.

The NESS H200 activates the muscles and reverses these secondary complications preventing long-term disability. "It provides regular exercise, like jogging, that can restore the limb to healthier function," said Nathan. "Sometimes a person can recover residual movements and gain spontaneous use of the hand."

The NESS H200 has been successfully marketed as the Handmaster in Israel and Holland for several years. It has been cleared by the FDA for marketing and sales in the U.S.

According to NESS researcher Amit Dar, the device had been tested extensively in Israel and the U.S.

"In Israel it was tested at the Lowenstein Rehabilitation Center and at Tel Hashomer in the Sheba Medical Center. In the U.S, we tested the device at the Kernan Rehabilitation Center in Baltimore," he told ISRAEL21c.

Approved in 2001 for functional use by the FDA, the NESS-H200 is now available in some U.S. rehab centers, and will become available in even more centers in both the U.S. and Canada over the next year. "It is sold through rehabilitation centers that are trained in using it," said Dar.

Dr. Gad Alon, a pioneer in stroke therapy and an associate professor at the University of Maryland School of Medicine in Baltimore, was responsible for testing the NESS-H200 at the university's Kernan center. In one of several papers, Alon and other researchers concluded in 2002 that the NESS H200 "is a safe and effective, noninvasive neuro-prosthesis for improving hand functions and impairments in selected persons with chronic hemiplegia [paralysis] secondary to stroke."

Last year, in a study that included 77 patients, some of whom had had strokes more than three years earlier, Alon and other researchers reported that "five weeks of daily home training using [the NESS H200] with a task-specific stimulation program is likely to improve hand functions and upper limb impairments" from stroke.

Melville, New York resident Saul Friedman participated in the clinical trials for the NESS-H200, and wrote about the experience for Newsday in Long Island.

"Whether the device, or the exercises or spontaneous recovery was responsible, I cannot say for certain. But after 12 weeks of electrotherapy and exercise, my hand remained open instead of becoming clenched. The blood flow in my arm increased, and serious swelling disappeared. In videotaped tests, I did increasingly well at moving blocks and empty cans from one place to another. Now, with exercise only, the hand function has continued to improve."

Shmulik Shany, CEO of NESS, notes that $1 million worth of orders have already been closed in North America, adding that the NESS H200 has been recognized in the Netherlands as a standard of care for post-stroke patients, and negotiations are now underway for a similar recognition by North American health-insurance firms.

The company lists Johnson & Johnson and Dow among its shareholders, and NESS recently set up a joint venture with Alfred Mann, the Alfred Mann Foundation and Advanced Bionics Inc., forming a new U.S. company, BIONESS, located in California.

By: David Brinn and Sharon Kanon
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Saturday, November 13, 2004

Detroit Institute In Line To Offer New Spinal Cord Procedure

The Rehabilitation Institute of Michigan in Detroit is hoping to become the first facility in the United States to offer a promising treatment for spinal cord injuries called olfactory ensheathing glia.

The procedure begins with cells extracted from the patient's nostrils. Scar tissue is then removed from the area of the injury, and in a five-hour surgery, the cells are injected into spinal cord at the injury site, where they regenerate.

"We are going to have something unique that no other center offers," said Dr. Steven Hinderer, of The Rehabilitation Institute of Michigan. "We're not there yet, but we're certainly headed in a good direction for it."

The best candidates for the procedure are people under 35 years of age with a complete injury, meaning no movement or sensation below the injury level.

The institute is meeting with the Food and Drug Administration in hopes of bringing olfactory ensheathing glia to Detroit in the next two years.
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Wednesday, November 10, 2004

Damaged Spinal Cord Grows Back

Mice with a spinal cord injury are walking again after a treatment that allowed their damaged spinal nerves to grow back, Australian researchers say.

The University of Melbourne and University of Queensland team says the treatment allowed the injured mice to walk within weeks of their injury.

The scientists say the research, which is to be published this week in the Journal of Neuroscience, is a major step towards mending spinal cord injuries in humans.

University of Melbourne's Professor Mary Galea and team found that removing the molecule known as EphA4 resulted in significant regrowth of the spinal nerves.

Mice without EphA4 regained their full stride length within three weeks of injury and within a month had regained ankle and toe movement.

Their ability to bear weight on the affected limbs and to walk and climb also improved for at least three months after the injury.

Galea said it would be some time before human tests could be conducted, but she described the research as the most promising in the area of spinal cord injury for years.

The team believes there is now scope for developing a drug that could block EphA4 in humans and stop a scar from forming on the spinal cord in the first place.

"In the first instance, I think we'll probably only be able to use this sort of drug in the very acute stages of spinal cord injury because the EphA4 is upregulated soon after injury so that's the critical point," she said.

"The emergency treatment would have to be done in the first few days after injury because we'd need to stop the EphA4 being released in significant quantities.

"Down the track it might be possible to look at people with older injuries."

She said it was likely new drugs would be tested on primates before humans and she expected it would be between five and 10 years before human trials were launched.

Another of the researchers Dr Ann Turnley said most people with spinal cord damage often suffered devastating effects and there was usually little chance they would ever regain much movement.

"In the past it was believed that adult nerves lacked the ability to regrow," she said.

"But work over the last few years has shown that not to be true and we are now beginning to understand the mechanisms behind regrowth and how to enhance it.

"Our recent findings are a major step forward in this regard."

How does the critical molecule work?
Scientists have known for some years that the EphA4 molecule was involved in guiding nerves while they developed. But scientists didn't know what the molecule did in adults.

Turnley said the team was surprised to find it was involved in activating cells called astrocytes.

These star-shaped cells are in turn responsible for scarring in the damaged spinal cord, which prevents the damaged nerves from growing back.

Mice without EphA4 have little scarring in their spinal cord, allowing the nerves to grow once more, the researchers said.
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Tuesday, November 02, 2004

Several New Techniques Show Promise for Spinal Cord Repair

Novel methods for transplanting cells into areas damaged by spinal cord injury and experimental drug treatments show promise for aiding those suffering from injury to their spinal cord.

New animal research brings increasing hope for sufferers of spinal cord injury, says Oswald Steward, PhD, of the Reeve-Irvine Research Center at the University of California, Irvine, College of Medicine. Studies are beginning to invalidate one of the longest held truths in medicine that nerve cells of the spinal cord are not able to regrow once damaged.

New research shows that a special type of cell transplanted into injured rat spinal cord forms myelin-the insulating material around nerves that speeds conduction of nerve impulses-and improves rats functioning, according to Masanori Sasaki, MD, Jeffery Kocsis, PhD, Karen Lankford, PhD, and Micheas Zemedkun, BS, in the department of neurology at Yale University School of Medicine.

Olfactory ensheathing cells (OECs) are specialized glial cells found in nerves and brain tissue associated with the sense of smell. Nerve cells within the olfactory tissue in the nose divide throughout life and send new axons-or nerve fibers-to transmit smell sensations to the brain. Scientists have long thought that OECs assist the normal regeneration of these axons and guide them into the brain where they make new functional connections. Because axons lose myelin after a trauma such as spinal cord injury, scientists have explored using OECs as a possible treatment. Several clinical trials to study transplantation of OECs into spinal cord injury patients are either ongoing or in the planning stages.

The Yale researchers obtained OECs from the olfactory bulbs of adult transgenic genetically altered rats expressing green fluorescent protein and transplanted them into other rats spinal cords that had been completely cut at the dorsal funicular location. The green fluorescent protein allowed the cells to be easily seen in the spinal cord.

The researchers observed groups of regenerating nerve fibers crossing the spinal cord injury site and the alignment of green cells forming myelin. Electron microscopic examination of the tissue showed that myelin was indeed produced around the axons by the transplanted cells. These results indicate that a number of factors including remyelination of axons may contribute to improvement in function following transplantation of OECs into the injured spinal cord, Sasaki says.

In other work, "tiny beads" (nanospheres) were found to release the enzyme that breaks down a component of the scar that forms after spinal cord injury. Dennis Stelzner, PhD, and his colleagues Donna Osterhout, PhD, and Julie Hasenwinkel, PhD, at SUNY Upstate Medical University and Syracuse University found that axonal growth, normally blocked by a component of the scar, is seen when the biodegradable nanospheres are injected.

Failure of axons to regenerate after spinal cord damage is attributed to a number of molecules present after injury that inhibit regrowth, including myelin (nerve covering) components and the scar tissue that forms after spinal cord injury, including the molecule chondroitin sulfate. "We hypothesized that it would be possible to remove the inhibiting elements of chondroitin sulfate with the enzyme chondroitinase ABC (cABC) by delivering this enzyme in biodegradable nanospheres to the spinal injury, and thus enhance axonal regrowth and recovery of function," Stelzner says.

Stelzner and his colleagues created and injected nanospheres (3 m l of 10 mg/ml of cABC) directly into eight different tissue cultures containing chondroitin sulfate that blocked axonal growth, and axonal growth was seen within two days. The cABC continued to be released for at least two weeks, assessed by analyzing its carrier molecule, as the nanospheres slowly degraded. Other experiments confirmed that the design of the nanospheres is effective in adhering the nanospheres to the chondroitin sulfate and that it has no toxic effects on cultured neurons.

The researchers are currently using these cABC nanospheres to treat spinal cord injury in rats. They have injected 3 or 6 m l of nanospheres immediately or one week following spinal contusion injury, or into uninjured spinal cord. Results so far show that the nanospheres remain near the injection site, and do not cause any major inflammation of spinal tissue, Stelzner says. "A unique feature of the nanosphere delivery system," Stelzner says, "is its ability to encapsulate other agents, in addition to cABC, that can be administered together, but released at various times, to counteract the inhibitory substances, and to target and promote regrowth in the spinal cord."

Aside from blocking the growth-inhibiting molecules present after injury to aid in spinal cord regeneration, nerve cells also can be altered internally so they no longer recognize the inhibitory molecules as hindering growth, and instead grow right through them. Marie Filbin, PhD, in the department of biological sciences at Hunter College and her team were able to use this approach to regrow spinal cord nerve cells using a drug called Rolipram.

First, researchers conducted in vitro studies in which nerve cells were removed from Rolipram-treated rats and exposed them to molecules that inhibited nerve regrowth. They found that if cyclic AMP (cAMP) a molecule found in every cell in our bodies was elevated in nerve cells, the blockers of growth did not inhibit regeneration. The drug Rolipram blocks an enzyme phosphodiesterase (PDE) that breaks down cAMP, thus inhibiting PDE , which leads to an accumulation of cAMP and nerve regrowth.

To treat seven female rats injured on one side of their spinal cords at the C3/4 location, researchers implanted embryonic tissue into the injury site to effectively fill the hole, and then administered 0.4 or 0.8 µmol/kg/hr of Rolipram via a mini-pump inserted under the animals' skin. The drug was delivered continuously for 10 days, beginning two weeks after the injury. Six weeks after drug administration, scientists found improvement in front paw control and movement and in nerve regeneration. Less of the scar formed in the Rolipram-treated animals as well.

In a control group of five rats, researchers placed only embryonic cells in the spinal cord injury site, without Rolipram, but no nerve cell regrowth or functional recovery occurred. "These results suggest that drugs that elevate cAMP (i.e., Rolipram), are likely to be effective in treating spinal cord injuries," says Filbin. As a result of Rolipram's success in regenerating spinal cord nerve cells, which was an off-label use at the time of Filbin's study, the company Renovis now has licensed patents on the drug Rolipram.

Another animal study demonstrated nerve regrowth and restoration of function of sensory nerves leading directly into the spinal cord, when two agents Zymosan and cABC were used in combination. Zymosan is an agent that is theorized to aid in the regeneration of neurons by escalating mechanisms responsible for neuronal regrowth. "Just as the inhibition of neuronal regrowth in spinal cord injury is caused by many factors, such as growth-inhibiting molecules and scarring, repair may be best achieved with several agents," says Jerry Silver, PhD, at Case Western Reserve University . "Combinations of agents to treat spinal cord injury may result in robust regrowth of spinal cord neurons."

Silver and his colleagues microinjected 31 µg/µl of Zymosan into one of the nerves (C8) of the upper limb of adult, female rats at the C8 dorsal root entry zone (DREZ) . Seven days later, the C8 dorsal root was crushed three times with #3 jeweler's forceps. Using a subset of 12 animals, the investigators microinjected 2 µl (20 U/µl) of cABC, in addition to the previous injection of Zymosan, directly where the nerve enters the spinal cord. Twenty rats received no injection, 10 rats received cABC injection alone, and eight rats received Zymosan injection alone.

Two weeks after nerve injury, the animals were euthanized and the neurons were labeled and analyzed for any regrowth from the injured nerve back into the spinal cord. The researchers also tested to see if the new nerves actually worked by performing motor evoked potentials (H-reflex) via stimulating the C8 sensory root and recording action potentials in the triceps muscles.

Eight of the 12 rats that received a combination of Zymosan and cABC had significant nerve regrowth, while two of the 10 rats that received the cABC alone, and five of the eight that received the Zymosan alone showed minimal regeneration. Untreated animals did not show evidence of regeneration through the dorsal root entry zone.

Furthermore, one-third of the group that received the combination Zymosan and cABC positively responded to electrical stimulation, confirming that the nerves that regrew actually worked. Re-severing the nerve resulted in a loss of the electrical response, which indicated that the response was truly due to the regrowth of injured nerves into the spinal cord. "The finding that nerves can regrow and actually work after injury," says Silver, "strongly suggests that the combination of Zymosan and cABC results in robust and functional regeneration of sensory nerves through the dorsal root entry zone following injury."
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