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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Advances Offer Hope for Spinal Cord Injury Patients

Cell transplantation, physical therapy show promise in restoring function

There is no cure for a spinal cord injury, but much headway has been made in clinical research that could lead to one. Other therapies have helped to restore some function in spinal cord injured patients. A look at some efforts?

The latest in cell transplantation

Cell-based therapies hold the potential for replacing cells and restoring function lost to disease or injury. Among those being developed to help treat spinal cord injuries:

Stem cells are building blocks capable of turning into various cells and tissues found in the body. Embryonic stem cells, in particular, are able to transform into any tissue, given the right biochemical instructions, and could be used to replace spinal cord cells lost during injury. However, human embryonic stem cell research is politically controversial, because culling the cells destroys embryos. Still in the research phase, stem cells have helped paralyzed rodents move again in several ways, including helping to regrow destroyed nerve cells in the spinal cord and successfully restoring myelin, a nerve fiber insulation that helps maintain the electrical conduction required to move.

Olfactory tissue, which covers about one-inch of the upper nasal cavity, contains many cells with regenerative potential, including olfactory ensheathing cells (OECs). Several experiments have found that OECs promote nerve regeneration and may restore function when implanted into an injured spinal cord. These OECs produce insulating myelin sheaths around the damaged nerve cells, encouraging regrowth. While research continues, some scientists, including Portugal's Dr. Carlos Lima, have transplanted olfactory tissue into patients with spinal cord injuries. Preliminary results were published in 2006 in the Journal of Spinal Cord Medicine.

Schwann cells: Another type of "ensheathing" cell, Schwann cells may also help stimulate nerve regeneration of an injured spinal cord. According to Dr. Wise Young, founding director of the W.M. Keck Center for Collaborative Neuroscience at Rutgers University, many laboratories have shown that Schwann cells alone will improve function after spinal cord injury in animals and even more so when they are combined with other therapies, such as OECs.

New advances in physical rehabilitation

Functional electrical stimulation: When connections between the brain and spinal cord are diminished by trauma, the ability to control movement can be eroded or lost. Functional electrical stimulation, or FES, systems can act as a substitute for those lost signals. FES systems apply a small electrical current that stimulates muscle contractions via electrodes that are either taped to the skin or surgically embedded. The contractions help maintain muscle mass, initiate movement in hands or legs or even stimulate the bladder or diaphragm. Dr. John McDonald of Baltimore's Kennedy Krieger Institute uses special exercise bicycles hooked up to FES systems to help paralyzed patients pedal, believing the repetitive activity helps restore function and also may stimulate regrowth of the damaged neural connections. McDonald also used FES in working with the late actor Christopher Reeve.

McDonald says: "We're focused on incremental improvements. What we ... say is this: No one can tell you whether you can walk or not walk. All I can say is doing an activity-based program in today's world is your best chance at meeting the cure halfway.''

Treadmill training uses repetitive motion to try to teach the legs how to walk again. A paralyzed person is suspended in a harness above a treadmill, reducing weight the legs have to bear. As the treadmill starts, therapists move the person's legs in a walking pattern. The theory driving the work is that paralysis causes "learned nonuse" of muscles, but the injured nervous system may be capable of recovery when certain conditions are optimized, including the patterned neural activity that accompanies treadmill walking. (Source: The Christopher and Dana ReeveFoundation Paralysis Resource Center.)

Activity-based, exercise or aggressive physical rehabilitation: Based on the same activity-triggering premise, several centers across the nation are using aggressive exercise, or activity-based therapy, to help restore function in some spinal cord injured patients. Results vary, depending on the patient's level of injury and how much time has passed since the injury.

But researchers like Young, of Rutgers, voice encouragement: "Many of the people who are currently not walking, if trained properly, would be able to walk. What is really necessary is more evidence-based medicine to indicate that these things really work and then to show to the insurance companies that this is an effective therapy so that they will cover it. Hundreds of thousands of peoples' lives would be affected.''

Centers include: Project Walk in Carlsbad, Calif.; BeyondTherapy, at the Shepherd Center in Atlanta; The Center for SCIRecovery at the Rehabilitation Institute of Michigan.

Pharmaceutical

Methylprednisolone, a steroid drug, became a standard treatment for acute spinal cord injury in 1990 when a large-scale clinical trial showed significantly better recovery in patients who were given the drug within the first eight hours after their injury. It appears to reduce the damage to nerve cells and decrease inflammation near the injury site by suppressing activities of immune cells. (Source: National Institute of Neurological Disorders and Stroke.)

Other drug-related research now under way includes: Studies to determine whether Riluzole, now used to treat Lou Gehrig's disease, may protect nerve cells and promote motor recovery when administered after spinal cord injury; and a trial involving the drug Cethrin, which has been found in animal studies to lessen post-traumatic neural cell death.

Gene therapy

Gene therapy carries the potential to provide the injured spinal cord with the specific gene products, or proteins, that it needs to promote functional recovery. Gene therapy is not a current treatment for spinal cord injuries but is being studied with animal models of spinal cord injury. The concept is to transfer into the spinal cord a gene encoding a therapeutic protein, such as a growth factor or an axon guidance molecule, or to transplant cells modified to incorporate the gene. When the gene is expressed, the cell makes the desired protein. (Source: "Spinal Cord Injury: Progress, Promise and Priorities,"' a publication of The Institute of Medicine, an arm of The National Academies.)

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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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Experimental Russian Stem Cell Treatments Credited for Woman's Progress

Experimental Russian stem cell treatments for spinal injury credited for woman's progress

Notice: The following excerpts are taken from the Grand Rapids Press. A link the the entire article is listed below, and is well worth the time to read.

When Kadi DeHaan took her first steps in December, two years after a car accident forced her into a wheelchair, she did it in typical Kadi style: low-key, nonchalant and with a confident grin.

Apparently, she knew all along she would walk away from her pink and black wheelchair and her customized leg braces, despite a spinal cord injury at chest level and a grim prognosis that she would never walk again.

It happened after two years of intensive therapy and six trips to Russia, where her stem cells were harvested and then injected into her spinal cord to restore nerves.

Kadi's progress is "very much a unique and wonderful thing," said physical therapist Sandy Burns, director of the Center for Spinal Cord Injury Recovery in Rockford, a clinic affiliated with the Detroit Medical Center.

No one can say for sure if nearly two years of experimental treatments or hours upon hours of physical therapy -- a trio of three-hour sessions every week -- led Kadi to where she is today.

Probably both, said Burns, whose clients sometimes head to Russia or Portugal or China for treatments that aren't approved in the U.S. and generally aren't covered by insurance.

The physical therapy is a very important component, "but it's definitely Russia," that put Kadi back on her own two feet, Kadi's mom, Bonnie, insisted. "There are just too many coincidences. Kadi knows that what she's got she got from Russia."

After fundraising dollars ran out more than a year ago, Kadi's parents took out a loan to pay for the trips to Russia. The three-year protocol recommended by Moscow doctors will cost in excess of $150,000.

At the time, Kadi had just a bit of feeling in her feet and could walk only with lots of help from custom-built leg braces and a walker.

Since then, she's given up the braces and is "tons stronger" and "a lot more independent," she said. She's a full-time student at Davenport University who quaffs Mountain Dew and confesses to sending text messages during class.

"I've seen a lot of changes. I've seen motor return, sensory return, everything," Kadi said.

She's so convinced of the gains made at the NeuroVita Clinic that she's planning her seventh trip there in August. Quite a change of attitude after she declared the first trip "the worst three weeks of my life."

Burns, who is quick to say her clinic does not endorse any of the alternative treatments, acknowledged that the stem cell injections do seem to make a difference, at least for Kadi.

"Folks that have gone there have, I think, consistently reported that they are noticing changes. They are feeling more," Burns said.

She tempers her optimism with the reality of what she sees every day: some of her clients will never accomplish half as much as Kadi has. Progress often depends upon the severity of the spinal injury, not just the region of the spine that was damaged.

That's why Burns doesn't make predictions about what her clients will eventually accomplish. But of course, she hopes Kadi continues to make great strides.

---

The Neurovita Clinic

Where: Moscow, Russia
What: Treats spinal cord injuries, degenerative disorders and some cancers with patient's own stem cells, which are harvested, grown and re-injected. Clinic moved away from use of embryonic stem cells because of compatibility issues.
Insurance: Because treatment is experimental and not performed here, U.S. insurance policies don't cover it.
Website: neurovita.ru/eng_index.html

The NeuroVita clinic was founded by neurologist Andrey S. Bryukhovetskiy in 2002. It's located on the campus of the Russian State Medical University and can accommodate 35 patients.

The clinic dabbled in embryonic stem cell treatments but now uses only autologous material -- that which is obtained from the patient -- because there are no problems with compatibility, not to mention politics and religion, according to the Web site.

About 11 of every 100 patients with spinal cord injuries walk again after the stem cell treatments, Bryukhovetskiy told them.

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Spinal Cord Implant

A team at University College London (UCL) is developing a spinal canal implant that could improve the quality of life and life expectancy for people with serious spinal cord injury.

Previous research has restored function to this patient group by stimulating muscles through the skin using surface electrodes or implanting electrodes in the muscles or between the spinal cord and the muscles.

UCL has for some time been investigating a different approach by putting the electrodes on the nerve roots, which is where the nerves emerge from the spinal cord but remain within the spinal canal.

'These are relatively fine and fragile fibres within the spinal canal,' said Prof Nick Donaldson of UCL's neuroprosthesis engineering department. 'The complication is that there are many fibres very close together which emerge from the spinal canal and form the major nerves that run down into the legs and also control the bowel and bladder.

'The advantage from a surgical point of view is that they're all available in one location, so you can, in a single procedure, field and place the electrodes together rather than having to fit electrodes and route cables over the legs of the patient.'

FineTech Medical makes an implant called the sacral anterior root stimulator for this site in the body which is just used for neurological functions ? primarily emptying the bladder and bowel.

'That has been very successful and made a big difference to patients who've had it fitted,' said Donaldson, 'but it doesn't do anything for the legs. I ran a research project in the 1990s where we stimulated the roots a bit higher up ? the lumbar roots ? and showed that we could get useful leg function, allowing a paraplegic to propel a recumbent cycle.

'We would like to expand the existing device by giving it more channels so we can add leg function to the existing neurological functions of the implants.'

The surgeon inserting the implant has to connect very small electrodes to individual nerve roots in such a way that the currents which flow between the electrodes just stimulate the target nerve roots, not neighbouring ones. This is achieved using a structure called an 'active electronic book,' because the surgeon can place the roots between the 'pages' of the device, separating them.

'The project, which is mainly technological, addresses how we can increase the number of stimulation channels without having many cables going into the spinal canal, said Donaldson. 'At the moment we have really been working at the limit of what the surgeons think is practical, with 12 channels, each corresponding to a nerve stimulated. The number one might want to stimulate is in the region of 20 to 30, so if we could double or treble the number of channels, we could do more for patients.

'That requires us having some way of putting the electronics right down near the electrodes. So the idea of the active book is that it has semiconductor switches and perhaps amplifiers within the electrode structure, we call the book and relatively few wires going through the dura (the outer membrane of the spinal cord) into the canal.'

This has the advantage of reducing the risk of infection and cerebro-spinal fluid (CSF) leak.

By the end of the project, the team hopes to show the technology can run in saline for long periods. It aims to demonstrate a method of sealing the electronics so the implant will be reliable for years, and carry out mechanical tests to prove its robustness.

The EPSRC-funded project runs from 2008 until 2010 during which time UCL will carry out the design of the electronics. When complete, approval will be sought from the Medicines and Healthcare products Regulatory Agency (MHRA) to undertake trials, which could take up to 10 years

UCL's project partners are the Tyndall Institute, which will develop the integrated circuit sealing, and Freiberg University, which has special knowledge of laser cutting tiny electrodes.

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Stem-cell therapy: Cure or hoax in China?

'Some get miracles'; others are skeptical

The website for Beike Biotechnology bursts with stories that can only be categorized as medical miracles: a paraplegic can move his legs again; a man with muscular dystrophy can carry a cup of water, a stroke victim can speak.

These tales of ailments treated come from all over the world - England, Hungary, Russia, Canada - and back the healing claims of a controversial Chinese treatment that purports to cure the incurable.

"I saw miracles every day I was there," says Leslie Wells, who flew to China in April, 11 years after a swimming pool accident rendered her arms and legs limp. "It can be a crapshoot. Some people get miracles, some people get nothing."

Doctors at Beike - based in Shenzhen, China - are treating a host of nerve disorders with stem-cell therapy, a procedure still under early clinical trials in much of the Western world. In just two years, doctors at Beike have injected stem cells from umbilical cords into the spines of nearly 1,000 patients from outside the country. Roughly 30 of those patients came from Canada, according to a Beike spokeswoman.

Approval for such treatments in Canada is years away, and the medical community here stands firmly opposed to people seeking them in China, citing possible health risks. In a research paper published in Neurorehabilitation and Neural Repair last year, several doctors in Canada and the United States followed up with patients of Hongyun Huang, who has been offering stem-cell treatments in China for several years. Few of the patients had improved since returning from China.

"If it sounds too good to be true, it's too good to be true," says Michael Rudnicki, Canada Research chair in molecular genetics at the University of Ottawa.

But increasing numbers of Canadians are sidestepping domestic regulations and venturing to China in hopes of a cure.

Ms. Wells, of Milton, Ont., first heard about Beike in a news story she read about two Ontario women who had suffered spinal-cord injuries in a car accident and then received the stem-cell treatments in China with some success.

As she flipped through the beaming testimonials on the company's website, it crossed her mind that the whole thing might be a scam. She just wanted a cure to nerve pain so crippling that "no painkiller known to man would help."

Her spine specialists warned her against it.

Eventually, she decided. "I was like, all right, what do I have to lose? Just a little money."

Ms. Wells paid $23,000 for the procedure and travelled to Nanshan Hospital in China, where she received six injections teeming with stem cells into her spinal fluid. Beike says the stem cells repair damaged nerves.

After her second injection, the pain that had made jobs and school seem impossible, was nearly gone.

"On a scale of one to 10, it went from like a nine down to a two. I haven't taken a single painkiller since."

She's not alone in her praise of the injections. With his speech and balance failing, George Arruda, an Ancaster, Ont., landscaper with ataxia, flew to Nanshan for four spine injections and two IV drips.

Ataxia is a progressive disorder that prematurely kills the nerve cells responsible for balance and co-ordination, and is one of the long list of neural conditions that Beike will treat. That list also includes epilepsy, ALS, cerebral palsy, spinal-cord injury and strokes,

Mr. Arruda knew it was an uncertain therapy, but his wife had recently given birth to a daughter. "I just wanted to be a healthy strong dad for her."

Before the trip, he could get around only with the aid of a walker. One night, about midway through his treatment, he was surprised to find himself walking to the bathroom unassisted.

"Immediately, I was about 20 per cent better," he says.

Since returning to Canada in February, he's had a relapse of symptoms. But he says that was probable considering the degenerative nature of ataxia. He's now looking at other stem-cell treatments.

Western medical experts chalk up the positive testimonials to the placebo effect. "We can give people a sugar pill and tell them it will get rid of all their pain and they'll insist that it works," Dr. Rudnicki says, "so I'm highly doubtful of testimonials. If I just spent $30,000 on a procedure, I would want to say it worked too."

Researchers at the University of Alberta are in the midst of studying the proliferating number of companies offering stem-cell cures. So far, they've discovered more than 30 based all over the world.

"The term stem cell has so much currency around the world right now," says Tim Caulfield, Canada Research chair in health law at the University of Alberta and member of a Canadian network of stem-cell researchers. "Even though the scientific community is deeply skeptical, people just associate the term with hope. It's a perfect area for quackery."

Eventually, Dr. Caulfield expects that researchers can use the University of Alberta study to make policy recommendations. "If there is fraud, we want to find it. The people going in for this are often tremendously sick and desperate. We want to ensure they are not being exploited."

Beike is open to the scrutiny. Patients are encouraged to post pictures and blog entries online documenting their time in China. Most depict a pristine hospital with cheery medical staff.

"Most of the doctors who work for us have been trained in Europe or the U.S.," says Kirshner Ross-Vaden, lead medical consultant with Beike's North American operations. "These are people who are leading the entire medical field. We have the nicest hospitals in China. The North American medical establishment is simply behind the times."

Beike says that 86 per cent of their clients show some measure of improvement.

Researchers in Canada say that while clinical trials have begun to look at the possibilities of stem-cell treatments, the therapies won't be available to the public for years - if they actually work.

Until that day comes, researchers here continue to advise against a stem-cell trip to China.

"They are ... putting patients at risk," Dr. Rudnicki says.

By: PATRICK WHITE

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Spinal Cord Injury Therapy Developed

U.S. medical scientists have developed a new spinal cord therapy that helps the body permanently recover from such injuries.

Researchers at the Sloan-Kettering Institute for Cancer Research studied rats with crushed spinal cords. The scientists found treatment soon after injury, combining radiation therapy to destroy harmful cells and microsurgery to drain excess fluids, significantly helped the body repair the injured cord.

The scientists, led by Nurit Kalderon, said their findings demonstrate conventional clinical procedures hold promise for preventing paralysis due to spinal cord injuries. Currently there is no cure for human spinal cord injury.

"This research opens the door to developing a clinical protocol for curing human spinal cord injuries using conventional therapies," said Kalderon.

The study, supported by a grant from the National Institute of Neurological Disorders and Stroke, appears in the online journal PLoS One.

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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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