Here's a great piece of clinically relevant research data that was funded by a Reeve Foundation grant and published this week by Milos Popovic.

For many years Popovic, at the Toronto Rehab Institute, has been working on electrical stimulation and neuroprosthetics to improve hand grasp and walking in people with spinal cord injuries. Functional electrical stimulation (FES) systems have gotten quite sophisticated and have been in use for a number of years, even commercially. But what Popovic found is quite remarkable: after a few weeks of FES therapy on hand function, a group of incomplete quads gained meaningful voluntary hand function without further need of the stimulation. In other words, the therapy seems to have reawakened arm and hand muscles – a biological revelation.

Said Popovic (pictured): "This is a seminal paper as it shows that one can dramatically change the hand function in SCI patients using FES technology. It also goes against the notion that SCI patients have to have surgeries, tendon transfers or neuroimplants to restore hand function (which is common belief in the field). Also, this approach is cheaper, has no side effects, has no pain involved, and every physiotherapist or occupational therapist can deliver it. "

Here's the experiment: Two sets of 12 patients were randomized – that means some get the treatment, others don’t. These were incomplete spinal cord injuries within the previous six months; none could grasp objects.

Function was measured using three tools: FIM, Functional Independence Measure; SCIM, Spinal Cord Independence Measure; TRI-HFT, Toronto Rehabilitation Institute Hand Function Test.

They all received conventional occupational therapy five days per week for eight weeks. Nine were randomly chosen (three didn't stay in the trial) to also receive an hour of FES therapy daily; the other 12 patients had an additional hour of conventional occupational therapy only. As reported in the paper, the patients who underwent FES therapy had "significantly reduced disability and improved voluntary grasping."

Those who got occupational therapy only saw a "gentle improvement" in their grasping ability. The measured improvement with FES was significantly greater.

From the paper:

We hypothesize that by providing both the command input and system’s output to the central nervous system repetitively over enough time, this type of treatment may facilitate functional reorganization within the sensorimotor network. It is important to add that during the intervention the subjects were performing grasping tasks repetitively. We believe that the combination of performing diverse and meaningful tasks with high repetition and subject’s persistent active engagement (all subjects had to devote 100% of their attention to the tasks performed) may have played a critical role in retraining voluntary grasping functions. These strategies are fully in tune with recent findings in the field of neuroplasticity and suggest that the proposed FET is potentially another effective method that can be used to retrain the neuromuscular system.

"What we now know is that through some interventions like this, you can actually change the way the brain operates to relearn the tasks that have been lost as a result of injury," he told a Canadian TV reporter.

Also from the report:

The positive results, as well as results of our preceding study, suggest that individuals with SCI would benefit from FET for grasping and voluntary hand function. We recommend at least 40 one-hour sessions of FET to try to improve upper limb function. Only after the patient has not shown signs of improvement should other invasive procedures be considered, such as implanted neuroprostheses for grasping and tendon transfers. We have trained more than 30 occupational therapists, physiotherapists, and biomedical engineers to administer the FET. Most of the physiotherapists and occupational therapists already knew how to use electrical stimulation systems, so minimal additional training, up to 2 hours, was needed. Donning and doffing the system requires no more than 5 minutes. From a logistics perspective, FET may be easily integrated into existing occupational therapy programs without requiring additional treatment hours or funds beyond those needed to purchase a programmable FES system.

Popovic noted that the study was limited in its follow up: "despite considerable effort we failed to attract the subjects to take part in a 6-month follow-up assessment. This can be explained by the fact that the majority of the subjects were discharged home or to long-term care facilities that were far from the study site."

The paper, “Functional Electrical Stimulation Neurorehabilitation and Neural Repair: Therapy of Voluntary Grasping Versus Only Conventional Rehabilitation,” appeared in the journal Neurorehabilitation and Neural Repair.

By Sam Maddox

Jorge Valdez missed a double front flip off a trampoline.

"I got lost in the air, and I landed directly on my head, and I just remembered feeling like fire," Valdez told a Miami news station.

He was taken to Jackson Memorial Hospital in Miami, paralyzed in the manner of full quadriplegia with only minimal arm function. Valdez, a 20-year-old college kid, wouldn’t have made a blip of a headline except that he was treated as part of a clinical trial by cooling his spinal cord. And also because a week later he walked out of the place. Doctors first feared Valdez was permanently disabled; after his recovery they said he would not even need any rehab. Read the story here.

Somebody was running a video camera; see him land on his head. (Photo courtesy of NECN.)

So, while the story is sandwiched between miracle and medical breakthrough, let’s look at Valdez's brief experience with paralysis, and the basis for systemic therapeutic hypothermia.

Valdez was treated by Steven Vanni, a neurosurgeon at Jackson. He is not on the faculty of the Miami Project to Cure Paralysis but a Project clinical trial protocol at the hospital is what prompted Vanni to rush Valdez to surgery to decompress the bones in his neck, and to immediately lower his body temperature from 98.7 to 92.3 degrees. This is done over a course of 48 hours using intravenous refrigerated saline. Cooling is thought to reduce inflammation by slowing down metabolism.

This isn’t a new idea. Cooling has been studied in SCI and brain injury since 1940. This is from a review of the hypothermia literature from ICORD (International Collaboration on Repair Discoveries) including Reeve Foundation Science Advisory Committee member Michael Fehlings:

…systemic hypothermia has been shown to be neuroprotective in patients after cardiac arrest, although its benefit in other clinical settings such as traumatic brain injury, stroke, and intracranial aneurysm surgery has not been demonstrated. Animal studies of local and systemic hypothermia in traumatic spinal cord injury models have produced mixed results. Local hypothermia was actively studied in the 1970s in human acute traumatic spinal cord injury, but no case series of this intervention has been published since 1984. No peer-reviewed clinical literature could be found, which describes the application of systemic hypothermia in acute traumatic spinal cord injury.

CONCLUSIONS: Animal studies of acute traumatic spinal cord injury have not revealed a consistent neuroprotective benefit to either systemic or local hypothermia…Although a cogent biological rationale may exist for the use of local or systemic hypothermia in acute traumatic spinal cord injury, there is little scientific literature currently available to substantiate the clinical use of either in human patients.

That’s just it. Hypothermia seems like a terrific idea. It saves lives after heart attacks. But there are a few things yet to work out in the central nervous system: How much should one be cooled, how long should the cooling last, should we cool just the cord or the whole body? It’s also very important to know how fast people should be warmed up again – too fast and there is risk of greater damage.

Dalton Deitrich, head of research at the Miami Project, hopes to prove hypothermia’s worth, good or bad. He’s already enrolled 20 or 30 patients, including, Valdez, in what is still a Phase I (safety) clinical trial there. The Project has submitted an application to the NIH for funding to expand the trial to other centers. From a Deitrich paper:

Moderate hypothermia has gained attention as a potential therapy due to recent experimental and clinical studies and the use of modest systemic hypothermia (MSH) in high profile case of spinal cord injury in a National Football League (NFL) player. In experimental models of spinal cord injury, moderate hypothermia has been shown to improve functional recovery and reduce overall structural damage. In a recent Phase I clinical trial, systemic hypothermia has been shown to be safe and provide some encouraging results in terms of functional recovery.

That football player is Buffalo Bills tight end Kevin Everett who hurt his spinal cord in 2007 and was systemically cooled with saline in the ambulance; he got a lot of immediate recovery, thus kickstarting the modern optimism for hypothermia.

As much as folks want to credit the cooling, even Everett’s doctor, Andrew Cappuccino, was restrained: "The extent to which this hypothermia contributed to his neurologic recovery is difficult to determine. It is hoped that this case will draw attention to the need for further preclinical and clinical studies to elucidate the role of hypothermia in acute spinal cord injury. Until these studies are completed, it is impossible to advocate for systemic hypothermia as a standard of care."

So, is there any reason to say cooling is what did the trick for Valdez? Kim Anderson-Erisman, Ph.D., Director of Education for The Miami Project, hopes people don’t take that leap. “We don’t want people to think the cooling cured him. The kid had an incomplete injury and he did get decompression surgery very early.”

Of course we join the trialists at Miami in hoping the cooling work pays off with a meaningful new acute therapy for SCI. Good idea, with a very nice outcome for at least two athletes, some encouraging headlines. But not enough yet for cooling to go mainstream.

by Sam Maddox

Induced pluripotent stem (iPS) cells are a discovery barely five-years old but they are one of the most compelling stories in biology. Many presumed these adult-derived cells would bypass embryos in stem cell science. New research suggests, however, that iPS cells are not as much like embryonic stem cells (ES) as first believed. They remain a transformative discovery, especially in disease modeling, but it will require a lot more study before iPS cells are as medically revolutionary as hoped.

iPS cells are adult cells, derived from skin or blood, for example, that have been back-programmed into an embryonic-like state. Induced cells look and act like remarkably like ES cells. They might be able, as an ES cell can, make all the other cells in the body.

The concept is fascinating: Take your own cell, morph it into an iPS cell which in turn can become a heart cell or nerve cell – a very nifty biology trick. Limitless replacement parts, no immune rejection. And of course the ethical bypass is obvious (no embryos, no Dickey Wicker). But according to a closer look by a group led by Joseph Ecker, a molecular geneticist at the Salk Institute, iPS cells have "hotspots" in their gene libraries that are not completely reprogrammed.

In other words, the Ecker paper (Nature) and two others last year from Harvard tell us that mouse iPS cells retain an "epigenetic memory" of the cell type from which they came. If you think of genes as cellular software, this means the iPS cells contain old code that can’t be overwritten and may therefore limit the ability of the new cell to transition cleanly to a new lineage. An ES cell, by contrast, has no code or memory until it is directed toward its fate.

Ecker et al looked at patterns of DNA methylation as a way to map gene exchange across the genomes of four human ES cell lines, five iPS cell lines and the tissues from which they were derived, plus a batch of differentiated cells made from both kinds of stem cells. "If you look with blinders on, they look fairly similar," said Ecker. "But if you zoom in you find different signatures of what an iPS cell is."

It shouldn’t come as a surprise that there are genetic aberrations in iPS cells, considering how their fate is manipulated. There are several ways to create iPS cells but the most common inserts a set of transcription factors into cells to recode them. This sort of thing has been going on since 1987 when scientists forced expression of genes in fruit flies that caused them to grow an additional set of legs instead of antennae. They used the same forced transcription factors to create functional eyes on the legs of flies.

In the much less ghastly iPS work of late, it only takes overexpression of four transcription factors to turn back the clock so certain cells seem new -- embryonic, unfated.

The fact that iPS cells are different than ES cells is not by any means throwing the iPS train off the tracks. Indeed, iPS cells that have a genetic vestige of their original programming might even be better as a therapy: for example, an iPS cell derived from blood might engender better new blood cells.

What’s more, iPS cells remain a critical tool for studying developmental biology. How did we wire up the first time, what are the codes, how do cells lock in to their fate? And importantly, how do cells go haywire and cause cancers? If only a few transcription factors can so dramatically change cell fate to make an iPS cell, might that mean there are simple breaks in the code that cause cancer cells? Scientists note that there are remarkable similarities between tumorigenesis and cellular reprogramming.

Meanwhile, what’s possibly the most exciting thing about iPS cells is the dawning of personalized medicine – therapies might be tailor-made from pluripotent stem cells from specific patients. It’s too still soon for that but for studying disease, iPS looks to be an extraordinary new tool. The metaphor scientists use is that of the flight data recorder: diseased tissues from patient-derived iPS cells permit a replay of the disease process in vitro. Perhaps it will be possible to predict or visualize destructive process. It may also be possible to screen chemical arrays to restore normal function and promote drug development.

That brings us to Fred Gage, a professor in the Salk's Laboratory of Genetics, whose lab is one of the Reeve Foundation’s elite International Research Consortium on Spinal Cord Injury. His lab has been using stem cells to study disease, and that includes spinal cord injury. Take a couple of minutes to see this video about how iPS cells can help understand what goes wrong.

Last week Gage received a $2.3 million grant from the California Institute for Regenerative Medicine (CIRM) to develop a stem cell based therapy for Parkinson's disease. His group will study iPS cells derived from people with the disease to replicate the disorder in the lab. They will investigate the role of inflammation and nerve degeneration that characterizes the disease. Until now, scientists were limited; they could study Parkinson's disease using imaging technologies or cadaver brain tissues. Now, iPS cells from patient skin cells, reprogrammed into neurons, will offer a model to study the pathology of Parkinson's in a human system. Ultimately, they hope to identify key molecular events in the early stages of the disease, with an eye on therapeutic intervention.

By Sam Maddox

By Sam Maddox

One of the major obstacles to recovery of function in chronic spinal cord injury is the failure of nerve axons to cross the lesion site, an area characterized by a scar-lined cyst filled with substances that repel axons. Several experimental models have found ways to detoxify the cyst by neutralizing specific molecular inhibitors, thereby promoting axon growth.

But it’s going to take more than that: the growing axons need some sort of scaffold or structure to guide them to make an appropriate connection. Enter the realm of bioengineering.

An interesting paper just came out (in ACS Nano: Transplantation of Nanostructured Composite Scaffolds Results in the Regeneration of Chronically Injured Spinal Cords) from a group in Italy working with engineers from MIT; they transplanted designer nanostructures to form a sort of 3-dimensional tubular neuroprosthesis six months after SCI in an animal model. Treated rats got a set of nanofibers (very, very tiny inorganic structures) transplanted into the lesion area, along with some unspecified cytokines to promote axon growth. The nerves reportedly grew and made functional connections.

Fabrizio Gelain, lead author for the paper noted, “Where usually in the damaged spinal cord there is scar tissue or a fluid filled cyst, nervous tissue regenerated and followed the direction given by our guidance channels. Histological results were also supported by significant functional recovery of the treated animals.”

What Gelain and his group found is that the implanted tubular channels to guided regenerating axons across across the cysts. The scaffold eventually was bio-degraded and there was negligible inflammatory response, said Gelain. “The nanostructured scaffolds led to the cyst being replaced by newly formed tissue, composed of both neural, vascular and stromal (support) cell types, that provided the appropriate environment for axonal regeneration and myelination, electrophysiological improvement and significant neurological recovery."

Gelain, working with stem cell researcher Angelo Vescovi, plans to add neural stem cells to the implant.

Meanwhile, the scaffold model is the focus of several other laboratory efforts. In 2007 a group in Hong Kong working with a spinal cord injury model transplanted a self-assembled nanofiber scaffold along with neural progenitor cells and Schwann cells. They reported “robust migration of host cells, growth of blood vessels, and axons into the scaffolds, indicating that the nanofiber scaffold provides a true three-dimensional environment for the migration of living cells.” They are also working on a brain procedure. A group in mainland China reported last fall that a co-transplantation of neural stem cells and Schwann cells along a polymer (poly lactide-co-glycolide acid) scaffold also promoted recovery in an animal model of SCI.

Boston-area biotech start up InVivo Therapeutics has based its entire business model on scaffolds for sub-acute (first few days) SCI. The company has applied for approval to transplant a biodegradable guidance structure invented by polymer guru Robert Langer of MIT. InVivo says it has successfully tested its device in nonhuman primates and hopes eventually to market polymer devices that also deliver drugs.

Scaffolds themselves will not be enough for significant recovery. It’s going to take a combination of treatments. Charles H. Tator, from the Toronto Western Hospital Research Institute, funded in part by the Reeve Foundation, has begun testing a novel four-part strategy to treat chronic SCI in animals. He starts with a transplanted guidance channel made of chitosan (naturally occurring and well tolerated by the cord) directly into the lesion cyst. The channel, 6 mm long and about 1.5 mm in diameter, features a scaffold made of fibrin – this allows axons nerve fibers to enter and grow along its course without inflammation or inhibition. The scientists are also adding spinal cord-derived neural stem cells to help guide fiber growth in and out of the channels. Finally, chondroitinase-ABC is injected at the ends of the channels; this enzyme dissolves chemicals that block axon growth.

Clearly, scaffold engineering and axon guidance are going to remain hot areas of research as biologists continue to find ways to spur growth or replace cells.

By Sam Maddox
The anti-cancer drug taxol appears to block inhibitory substances and reduce scarring after spinal cord injury. The drug, derived from the bark of the Pacific yew tree, is commonly used to treat several types of cancer, including breast, ovarian and lung, as well as Kaposi's sarcoma in people with acquired immunodeficiency syndrome (AIDS).

It works by as a mitotic inhibitor, thereby preventing cancer cells from dividing. In spinal cord injury experiments with acutely injured animals, taxol is used in a lower dose that does not block cell division; it appears to reduce the effect in inhibitory substances in the area of injury. How so? In cancer the drug ties up microtubules, the “bones” of the cytoskeleton or cell structure. In the spinal cord, taxol is believed to stabilize these microtubules and therefore maintain the architecture of nerve cells. It also appears to kick-start axon growth.

It is well known that axons can’t regenerate in the lesion area of the spinal cord due to a host of inhibitory factors and glial scarring. There have been many studies showing robust regeneration if the lesion area is modified. Currently in clinical trial is a molecule that targets the inhibitor NOGO and blocks it out of the way so axons can pass by. Other possible treatments to reduce inhibition include the enzyme chondroitinase ABC, which targets scarring. Strategies also include reducing immune response.

The taxol work came from an international team, including scientists at the Miami Project and Kennedy Kreiger Institute. PI (principal investigator) was Frank Bradke of the Max Planck Institute of Neurobiology in Germany.

Verbatim from the published abstract:

Moderate microtubule stabilization decreased scar formation after spinal cord injury in rodents via various cellular mechanisms, including dampening of transforming growth factor–β signaling. It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth competent sensory neurons. Microtubule stabilization also promoted growth of central nervous system axons of the Raphe-spinal tract and led to functional improvement. Thus, microtubule stabilization reduces fibrotic scarring and enhances the capacity of axons to grow.

Here’s what Bradke told the press about inhibitory factors, taxol and SCI: “Inhibitors act like stop signs for these axons.” He said the idea is to either take away some of the stop signs, or get the nerve cells to act like a “mad driver” and ignore them.

“The good thing about taxol is that it actually does both things at once,” Bradke said. “On the one hand, it basically gets these neurons to start to grow, like a crazy driver, and at the same time, it also reduces these stop signs, it reduces the scarring process. With taxol, he said, “You basically manipulate the two major impediments to axon regeneration.”

In rats, taxol decreased the amount of scarring in axons, and stimulated their growth more than placebo. It also improved function; injured rats treated with taxol frequently made fewer missteps on a specific walking task, Bradke said. This work is still early and has not been tested in people, but Bradke pointed out that taxol is already approved for human use, which could speed the process of clinical trials along. “We are still in the state of basic research and a variety of obstacles remain - and eventually, pre-clinical trials will need to be done,” said Bradke. “However, I believe that we are on a very promising path.”

The Bradke paper, Microtubule Stabilization Reduces Scarring and Causes Axon Regeneration after Spinal Cord Injury, was published January 27 in Science Express, the advance online publication of the journal Science.

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