The track record for spinal cord injury cure research isn’t so hot. It’s not very long, either. No clinical trial has ever proven structural or functional recovery after SCI; moreover, functional regeneration hasn’t been shown in larger animal models. No such clinical trial has ever made it through phase III of the FDA process, the necessary step before it can become a treatment. But the science behind repair or restoration of the paralyzed body is more energized than ever.

Cartoon Cures
Several human clinical trials are happening now, in both acute and chronic SCI, and more are coming. For the first time, the long slog toward treatments is moving beyond basic science into the hands of industry and commerce.

First, though, about the word “cure”: It doesn’t work — at least when it comes to spinal cord injury. While it used to pretty much mean restored walking, I’ve heard it said a cure is getting so much back a stranger can’t spot any disability. That is a pretty high bar, and for all but very incomplete injuries, asks too much of modern medicine.

If you’re like many people, there’s an overly simple cartoon running in your head, the one about how cure medicine works: one treatment, axons grow, everybody walks. The old American Paralysis Association had a stick figure getting up from his wheelchair; the Miami Project still employs the stick guy, showing incremental progress toward taking a step. APA kept its iconograph going until the mid-1990s, when Christopher Reeve came aboard, at which time he became the living logo for cure, upping the ante on recovery. He challenged the biomedical research community to get a move on, while declaring that he’d be playing tennis by age 50, and then rising up to walk across the room in a computer-generated ad shown during the 2000 Super Bowl.

My own cure cartoon came by way of the Spinal Cord Society 30 years ago. At one of their summer conventions, guest lecturer Eric Shooter, a Stanford scientist and early SCI cure optimist, imagined the broken circuitry of the spinal cord being healed by soaking in a magical cocktail of nerve vitamins. In other words, fertilize the garden and axons will bloom, grow and make nice new connections. Bogus, yes, but not completely irrelevant; many scientists carry on the work of optimizing that axonal garden with cells, bridges, scaffolds and indeed, nerve vitamins. They’ve also learned, though, that the problem is with the axons themselves — their intrinsic inability to grow and connect. I’m now seeing molecular switches activated by gene cues emerging from an implanted Trojan horse.

The dominant cartoon today is without a doubt that of a potent stem cell infusion, right out of “nature’s toolkit,” to replace or repair spinal nerves and make things good as new. Squirt the cells in there and watch them home in on the hearts, brains, cords, cancers, the whole grab-bag of disease and trauma. The stem cell cartoon has become so ingrained in the public imagination that well-meaning but poorly informed cure seekers travel the globe and pay huge sums of money to unregulated and often shady clinics doing experimental cell procedures that purport to fix nearly every health issue. (Potential stem cell tourists, please see the International Society for Stem Cell Research website: www.closerlookatstemcells.org.)

The Intelligent Cord
Reggie Edgerton is a scientist at UCLA who has been studying spinal cord issues long enough to know the old cartoons don’t work. He’s a very careful investigator, quite cautious about misguiding the press or public on results of his experiments. Wouldn’t want to be putting out false hope. His primary work with spinal cord circuitry underpins one of the bigger SCI stories in recent years: The spinal cord is a series of circuits and not just a telephone wire from the brain to the rest of the body. It is in fact part of the brain, and smart; moreover, sensory input, e.g., activity, can trigger useful patterns and movements.

Two years ago Edgerton’s lab published what many considered a “breakthrough” paper in Nature Neuroscience, a top-tier journal. His team showed, for the first time, rats with completely severed spinal cords walking on a treadmill with near normal gaits, bearing their full weight. The walking was facilitated not by restoring brain control, but by exploiting circuitry in the spinal cord itself. The rats got a triple whammy of treatments: a combination of a drug to enhance nerve transmission, epidural electrical stimulation of the spinal cord, and lots of treadmill training.

More rats walking, oh boy. Why is this a breakthrough? Because it shows that the sensory system, not the brain, can actually control complex activity and stepping: The animals could step sideways, backwards and vary speed. There’s a lot of what Edgerton calls “automaticity” in the spinal cord: We don’t have to think about movements, the cord knows what to do. “After injury, we just have to remind it.”

Last December the Reeve Foundation held a symposium in Phoenix wherein 100 or so scientists funded by Reeve discussed their work while members of the SCI community got to hang out, chat, eat and drink wine with them for a weekend. Science becomes humanized and medical research is demythologized, at least a little bit. Many of the scientists, some who had never really met a person in a wheelchair, gained perspective and perhaps a sense of urgency.

Edgerton, whose work is partly sponsored by Reeve and who considers himself “a little more optimistic than most,” presented a lecture called “Time to Pick the Fruit” — a statement, not a question. In other words, after a career spanning nearly 40 years in basic research, Edgerton suggested maybe it’s time to capitalize on science by taking some of the results to the clinic, that is, to the folks in the chairs. He’s already considered one of the pillars of the activity-based rehab movement and was a co-founder of the NeuroRecovery Network, a Reeve initiative to better understand how treadmill training can activate stepping and trigger numerous health benefits.

And those triple-treated rat experiments? Edgerton and his group have already begun to test two of the three parts — epidural stimulation and aggressive rehab, with the drug part coming soon — in a single individual. This is the fruit he’s hoping ripens soon. With a work in progress, Edgerton is not going to spill the beans ahead of the usual peer-reviewed publication process, but clearly excited, he told the symposium crowd his group is very encouraged by the response of the first human subject.

Edgerton’s group is seeing what activating spinal circuits can do without any connection from above the lesion. “Let’s assume someone figures out how to get axons across the lesion,” he says. “Now when that happens — that connection taps into the spinal cord circuitry — the results can be quite big.”

Edgerton listed a few other possible fruits to pick, including olfactory ensheathing glia and chondroitinase ABC. The OEG story is well known: self-replicating nerve cells from the nasal area may have a restorative effect on other central nerves. When placed in the lesion area of the spinal cord, some benefits have been shown in clinical trials. People have been getting this done for many years in Portugal. OEG cells alone probably won’t be a mainstream intervention. But add growth factors or other molecules to sweeten up the injury site, and this might pan out.

ChABC is an enzyme that helps break up the scar tissue in the lesion site and therefore allows axons to move across it. The drug has been widely tested in recent months — it improves basic and skilled locomotion in spinal cord injured cats. ChABC will likely be used in combination with OEG, Schwann cells or other cell transplants, growth factors or scaffolds for axon growth, and always, rehab.

James Fawcett, who like Edgerton runs one of the Reeve Foundation’s elite Consortium labs, says he’s just about ready to go on human trials for ChABC. The drug will be supplied by Acorda Therapeutics, well-known in the SCI world for refining the nerve signal booster drug 4-AP, which, for SCI, was deemed clinically irrelevant by the FDA. The company did get the drug (now Ampyra) approved last year to treat MS; therefore it’s on the market, off label, for SCI.

Other labs are working on the scar issue. Steven Davies at the University of Colorado, Denver, says he’s moving toward clinical trials in the chronic SCI population for the drug Decorin, in combination with an adult stem cell called glial-derived astrocyte. In animal models the combo provided “robust axon growth.”

The Fruit of Axon Growth
Edgerton labeled another of his fruits PTEN. This refers to the work of Zhigang He of Children’s Hospital, Harvard, and Oswald Steward and his research group at the University of California, Irvine, where he heads the Reeve-Irvine Research Center. Their collaboration initiated the Corticospinal Tract Regeneration Project. This, says Steward, is to develop ways to promote regeneration of the connections that control voluntary movement. “Even a small amount of regeneration of this pathway,” says Steward, “could have a huge functional benefit for people paralyzed as a result of injury.” Last September his team published a paper in Nature Neuroscience — they even landed the cover photograph — showing that deletion of a gene called PTEN turned on a switch allowing neurons of the corticospinal tract to regenerate through a complete spinal cord injury. The image of the axons crossing the lesion is indeed striking. “Nothing like this has ever been done before,” Steward said.

The paper has been called a major advance in promoting recovery of spinal cord injury. But can it be moved forward as a potential therapy? First, they have to show that the cortical regeneration improves motor function. Second, they have to show PTEN deletion works after a spinal cord injury — animals described in the paper had the PTEN gene knocked out genetically, before injury. Third, can it be made to work in humans? They are looking for drugs that might block PTEN, or perhaps an anti-gene delivery system. It’s a long way to go before fruitfulness.

Bob Yant, the veteran cure warrior, has been helping Steward and Zhigang raise money to continue the basic work. “In the 30-some years I’ve been a cure advocate, this is something I find so compelling, so promising, I knew I had to devote my efforts to it. You could say others have regenerated spinal nerves before, but this, in comparison, shows just a huge amount of axon growth. The difference with the PTEN story is magnitude.”

Stem Cells: The Short Horizon
Last on Edgerton’s short list was stem cells. Geron and the dawn of the human embryonic stem cell era dominated the SCI cure discussion the past couple of years. After a much-delayed and lengthy process, the company finally got FDA approval to test an injected cell derived from embryonic stem cells into newly injured (less than 14 days) paraplegics. The first was treated at Shepherd Center in October.

The goal of the trial is safety. But anybody following cure knows the stated secondary endpoint is neurological function. And they know about Hans Keirstead, how he is the one who came up with these stem cells and how they made rats walk and how he and his rodents helped sell California voters on Proposition 71, the $3 billion stem cell bill. (If you’re wondering why the science in this article seems so West Coast, that’s why: more money, more research).

Keirstead is trying to move as fast as anyone from experiments to therapy, and for that, and for showing treated rats in a video before publishing the results, he’s been labeled a cowboy. The New York Times called him the Pied Piper of stem cells. In the SCI world, however, Hans is the prince of progress. “We love how Hans is so wonderfully aggressive,” says Karen Miner, whose organization, Research for Cure, raises funds for the Reeve-Irvine center’s Hans Keirstead Research Group. “We adore him.”

It still took 12 years for Keirstead to see his stem cell gambit reach a phase I trial. He and his team at UC Irvine began testing stem cells for spinal cord injury in 1999 and had completed the basic animal research in 2004. They coaxed human embryonic stem cells into oligodendrocyte progenitor cells that, when transplanted to the injury site in an acute SCI model, helped injured axons to remyelinate and therefore work more normally. He got the paper published in 2005, showing that robust functional recovery occurred.  Geron, which also funded the work at the University of Wisconsin, Madison, that led to the original lines of human embryonic stem cells, licensed the UC Irvine work. Five years, hundreds of lab animals, zero teratomas (tumors), $45 million and 22,500 pages of FDA preclinical paperwork later, the company was first out of the gate with a potential embryonic stem cell therapy.

Of course there are those in the neuroscience community who felt a big error now could damage the field, that it was too soon to take Geron’s cells to trial. Also, the politics around embryonic stem cells are not going away. Witness last year’s federal research halt because of the 1996 Dickey-Wicker Amendment, which prohibited the use of federal funds in which a human embryo or embryos are destroyed. But more trials are on the way:

• Based on Keirstead’s continued work with embryonic stem cells, California Stem Cell Inc. and Families of Spinal Muscular Atrophy applied to the FDA to use stem cells to treat SMA, often fatal in very young children. This will look at a motor neuron transplant and will be of great interest to people with SCI and ALS, since, Keirstead says, “we developed this specifically for chronic spinal cord injury.”

• Aileen Anderson and her husband, Brian Cummings — Keirstead’s colleagues at Reeve-Irvine — got the OK last December from the Swiss equivalent of the FDA to test stem cells in Zurich, in “early chronic” (3-12 months post-injury) paraplegics, both complete and incomplete. Animal tests indicated walking recovery. In collaboration with Palo Alto-based Stem Cells Inc., the trial is billed as the world’s first human treatment using neural stem cells derived from aborted fetuses. Anderson thinks this is a better bet against tumors, since the fetal cells are restricted to being nerve cells. “They can’t make — as embryonic stem cells can — bone cells, muscle cells, blood-derived cells,” she said. Of interest to the stem cell research field, this approval was made quite quickly, in less than two months.

• The first FDA approved trial for chronic complete spinal cord injury began with little fanfare last August in a small clinic in Covington, La., about an hour north of New Orleans. The trial, set up and paid for by TCA Cellular Therapy, is testing the safety and efficacy of cells derived from bone marrow and injected by lumbar puncture into the spinal fluid. Technically, these are called autologous (from the person’s own body) mesenchymal (multipotent) stem cells (MSC) and are indeed a type of adult stem cell. TCA was formed by South American-trained cardiac specialists with no experience in spinal cord research. They made the request to the FDA for spinal cord injury after getting five other trials approved to test MSC in heart disease, peripheral vascular disease, peripheral arterial disease, limb ischemia, and ALS. Two people have been enrolled in the SCI trial, the first being former U.S. Marine Matt Cole, five years post-injury. TCA is hoping the MSC injections can differentiate into nerve cells and/or provide a neuroprotective effect that might activate repair or rejuvenation. The company reports that Cole, 30, who by chance lives in Covington, has recovered some superficial and deep sensation in the lower legs. “It’s positive that there may be bigger things to come,” Cole said. TCA is pretty sure about its clinical results: they’re already offering MSC as a therapy, ahead of FDA’s blessing, for those who may not qualify for the trial. The reported fee is $20,000.

• China network: Umbilical cord cells plus the drug lithium are being tested in a clinical trial in China. Wise Young, the CareCure Internet community patriarch from Rutgers, set this network up and hopes to bring the trial to the U.S. if it shows promise. Lithium, he suggests, activates the cord blood cells.

Lots of clinical trials does not mean lots of therapies on the market soon. Some, perhaps many, trials will fail. But there is reason for optimism. I have heard this phrase many times in the last year from scientists:  “Perfect is the enemy of the good.” In other words, the whole solution is clearly not possible, but let’s start taking aim at its smaller parts.

Those cartoons, they have a chance. Cure — or cures — are coming.

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Basic Neuroscience
Initial injury to the spinal cord (almost never severed, usually a bruise) kills some nerve cells and disrupts connection between brain and body. But there’s plenty more to it: inflammation, immune response, blood loss and all sorts of chemical chaos at the injury site continues to degrade nerve cells. This second phase, in theory preventable, is the focus of acute SCI therapies. Only one has been approved for SCI — methylprednisolone, a steroid that may affect inflammation. But there are at least three more acute therapies in clinical trial now: Geron’s embryonic stem cell trial; the neuroprotective drug Riluzole in the North American Clinical Trial network; and anti-NOGO, a molecule that clears the way for axon growth. Other ideas may also be headed to trial, including statin drugs, cooling and immune modulation.

After the secondary cascade settles, the injured area of the cord typically becomes a scar-lined cavity.  Surviving nerve cells try but can’t cross the cavity or penetrate the scar — unless, experiments have shown, they have the right bridge, the right scaffold and the optimal cellular environment. Trials are on track for several bridging concepts (e.g., Miami Project’s plan to use a Schwann cell bridge; InVivo’s pending trial using a polymer cell scaffold).

Long axons that control movement of legs originate in nerve cells in the brain, and after injury, shrink back to the cell body. Restoring these major motor nerves the length of the spine — and across the lesion area — is considered the holy grail of neuroscience and quite a daunting task, and while beyond the scope of today’s science, it’s not beyond the imagination of scientists. Steward at Reeve-Irvine is looking at longer regeneration, as is Mark Tuszynski, a scientist at UC San Diego. Tuszynski’s gene delivery work is partly the basis of ongoing clinical trials to treat both Alzheimer’s and Parkinson’s diseases with nerve growth factors.

Regeneration in the chronic injury will require a combination therapy, including modification of the neuron cell itself and also of the non-permissive injury environment.

Some axons in the lesion area are alive but non-working. Many are demyelinated. They may need to be cultured within a less hostile environment. There are ways to neutralize the scar and to support robust growth by modifying the toxic chemistry of the lesion area. Chondroitinase ABC, an enzyme that eats up scar, has promise. Stem cells might do the job, too, acting as protective cells.

Treatments that affect segmental function in the area of cord damage will likely be most optimal in quads. For example, if a bridge or cell transplant could restore two segments of function, this would enable a C5 quad to independently transfer — a huge benefit.

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Charles Carson, Early King of Cure
Hyena. Charles Carson said I was “a hyena preying on the bones of misery.” I met him back in the 1980s when he used to host an annual spinal cord injury research gathering; he thought I was trying to hustle his Spinal Cord Society minions with information about paralysis that made it look “fun.” I was, therefore, part of the great conspiracy in the medical and rehab world to “keep people paralyzed because there is too much money to be made.”

Carson died last October. He was 75. It is sad he never got to taste the fruit of more than 30 years of strident cure activism.

He was hurt in a plane crash in 1976. Two years later he founded the Spinal Cord Society, with its iconic X through the wheelchair logo: cure not care. He used to say, “A lot more people have died from no hope than from false hope.” He always had hope, but he wasn’t the roll model type.

Carson used to write about people with disabilities having a “Damascus experience” and therefore coming to terms with their new reality. He himself never had such a conversion.

He set up a chapter network, raised about $1 million a year and dutifully pumped out his sometimes chatty monthly SCS newsletter. He didn’t reach out to other organizations and didn’t trust industry or government to get the job done. He alone decided what scientists to support. To his credit, Carson’s early funding allowed Jerry Petrofsky, beginning in 1982, to pursue computerized walking and FES bikes. He was a huge sponsor of Richard Borgens (electrical fields that promote regeneration) at Purdue, until suddenly he wasn’t. In recent years SCS has supported its own lab, a small team in Fort Collins, Colo., working on strategies to bridge the lesion area; that work will continue.

“Carson was a pioneer,” said Paul Richter, who formed the New York chapter of SCS in the 1970s. “He was tough as nails but as sensitive as a good grandpa. A good man.”

Carson did it first, and he did it his way. According to a longtime associate, he went in to the hospital in October with pulmonary fibrosis. His doctor also suspected pneumonia and recommended antibiotics.  Maybe it’s because he didn’t trust the doctor, or the hospital, or the pharma industry, who knows? Carson wouldn’t take the medication and died within 12 hours.

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