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Chronic SCI Stem Cell Trial Set At UCSD

A team at the University of California, San Diego School of Medicine, backed by the young biotech company Neuralstem, recently launched a clinical trial to assess the safety of neural stem cell transplants in patients one to two years post spinal cord injury. The Phase I clinical trial is recruiting four patients.

UCSD began recruiting August 11. Here is the trial detail from Clinicaltrials.gov. Says trial contact Amber Faulise, response to the call for participants has been quite robust -- dozens of potential patients have already been initially screened. Besides the small window for injury timing, only complete injuries from T7 to T12 are eligible. Since the trial is small, and first come first serve, it’s probably too late to have a good shot at participation. But Faulise says as of August 22, the UCSD team is still open to inquiries, and is keeping an in-house database for future clinical options.

All patients in the trial will receive six 100,000-cell injections in or around the injury site, using the same stem cells (the company calls them NSI-566) and procedure as in Neuralstem’s ALS trial. All will also receive physical therapy post-surgery and will be measured before and after to compare sensory and motor index scores, bowel and bladder function scores and evoked sensory or motor potentials. Graft survival in the transplant site will be determined by MRI.

From a press release:
“The goal of this study is to evaluate the safety of transplanting neural stem cells into the spine for what one day could be a treatment for spinal cord injuries," said Joseph Ciacci, MD, principal investigator and neurosurgeon at UCSDS. "The study's immediate goal, however, is to determine whether injecting these neural stem cells into the spine of patients with spinal cord injury is safe."

Related goals of the clinical trial include evaluating the stem cell graft's survival and the effectiveness of immunosuppression drugs to prevent rejection. The researchers will also look for possible therapeutic benefits such as changes in motor and sensory function, bowel and bladder function, and pain levels.

All participants will receive the stem cell injection. The scientists will use a line of human stem cells approved by the U.S. FDA for human trials in patients with chronic traumatic spinal injuries. These cells were previously tested for safety in patients with amyotrophic lateral sclerosis (ALS).

Pre-clinical studies of these cells by Ciacci and Martin Marsala, MD, at the UC San Diego School of Medicine, showed that these grafted neural stem cells improved motor function in spinal cord injured rats with minimal side effects indicating that human clinical trials are now warranted.

This is certainly exciting new territory for SCI therapy development – you don’t see trials for chronic injury very often – but it’s fair to ask some of the basic questions you would regarding any stem cell therapy. What is the source of the cells; what pre-clinical research supports the trial; what is the mechanism of action; and what are the risks?

Source: The cells are a line of cells Neuralstem batched up 8 or ten years ago, derived from the nerve tissue of an unborn fetus (technically, that means these are adult and not embryonic cells).

Pre-clinical: There have been several experiments Neuralstem likes to cite as a foundation for the trial, showing that its neural stem cell line integrates with host tissue to create new nerve pathways. The most compelling set of experiments was reported in the journal Cell, September 2012, by Paul Lu and his team at the UCSD lab of Mark Tuszynski. This paper, Long-Distance Growth and Connectivity of Neural Stem Cells after Severe Spinal Cord Injury,” was featured in our blog here. The paper made four key points, from the abstract:
  • Neural stem cells grow axons over very long distances after severe spinal cord injury
  • New synaptic relays are formed, improving electrophysiological and functional outcome
  • Rodent and human neural stem cells exhibit similar growth properties
  • Mechanisms intrinsic to early-stage neurons overcome adult nervous system inhibition
Lu tested the Neuralstem human cells in the rats and showed tremendous growth of axons in animals with completely severed cords. Recovery of function was evident, but modest (not as far as weight bearing).
 
There are a couple of key differences, however, between animal research to date and what is planned in the human trial. The animals in Lu's experiment got stem cells transplanted two weeks after injury. That’s certainly not an acute model, but is it comparable to a human chronic injury 12 to 24 months out?
 
Also, Lu had tried stem cell transplants for years until he got them to stay where he put them in his animal models. To finally do that, he devised a fibrin glue injection as a sort of scaffold. It worked; the cells remained. In his Cell study, he also dosed each rat with a combination of ten growth factors and nutrients. The humans just get the cells, no glue, no juice.
 
There’s one more thing we should mention about the Lu-Tuszynski paper from 2012. In an attempt to replicate the findings of axon growth and recovery of function, Oswald Steward ran the same experiment at his lab up the road at UC Irvine. Steward doesn’t do this for fun; he has a grant from NIH to independently replicate key SCI studies. Well, Steward didn’t get same result his friends at UCSD got. He published a paper, "A re-assessment of long distance growth and connectivity of neural stem cells after severe spinal cord injury,” noting:
There was extensive outgrowth of GFP labeled axons from the graft, but there was minimal ingrowth of host axons into the graft revealed by tract tracing and immunocytochemistry for 5HT. There were no statistically significant differences between transplant and control groups in the degree of locomotor recovery. Our results confirm the previous report that NSC transplants can fill lesion cavities and robustly extend axons, but reveal that most grafts do not create a continuous bridge of neural tissue between rostral and caudal segments.
 
Steward's paper doesn’t invalidate the UCSD work, but just goes to show that animal research has its limits. It does not produce exacting recipes for success – in other animals, or in humans.

Neuralstem CEO Richard Garr writes a blog at the company website. Last week, he more or less admitted the preclinical data is less than rock solid.
We are, of course, still very early in the process and, in this area in particular, there is a history of promising preclinical starts that have never translated into improvement in humans. So we must view the preclinical data with caution and some skepticism. But at Neuralstem we are not afraid to raise the bar on expectations. 
 
Mechanism: How do the cells work? Speculates Neuralstem CEO Richard Garr: “...we are actually counting on our cells to ‘rewire’ the injured cord and reestablish a connection from above to below the injury.” He said he knows this can occur because of the Lu paper we just spoke about. “We are confident that our cells can in fact create new circuitry and allow for some signal to ‘bridge the gap’ created by these injuries.” Well, remember, no glue, no cocktail, so maybe not.

Garr also mused that his company’s SCI trial hopes to expand upon other promising clinical data, specifically recent epidural stimulation research (The paper in Brain from last spring, e.g. the four guys who could voluntarily move their legs when stimulated, heavy support from the Reeve Foundation). From Garr’s blog:
Even if our cells allow the signal coming “down” the spinal cord to now get through the “break” area, will the circuitry leading “out” to the muscles still be intact and operational?  In animals, it seemed clear that the answer was yes, but as mentioned those studies are always “acute” in terms of the time from the injury.  There was simply no way to know what the situation was in humans a year to two years out from the injury.
 
Now however, there is good evidence that, in fact, that circuitry is still intact and operational.  In a study reported in the April 8th, 2014 online neurology journal, Brain, researchers at UCLA and the University of Louisville demonstrated that chronic human SCI patients could have their lower limbs “activated” through epidural/electric stimulation. The results were extremely limited, but clear. The peripheral circuitry and muscle groups that were innervated were still capable of operating. This is very good news for our program. We now have the answer to the last “missing piece,” so to speak. We know now that if we CAN get the signal through the site of the injury back down to the rest of the cord, the remaining system has not atrophied past use. If this were not the case, then all the signal in the world coming “down” may not have provided a benefit for the patients. 
 
Risk: Because Neuralstem has used the same neural cell line in numerous human patients with ALS, involving more than 30 spinal transplants, the safety profile is pretty well established. There were no adverse events reported. The greatest risk in the SCI trial will probably be infection. Surgeons are always wary of infection; in this case, even more so because patients are immune-suppressed for three months. This helps to avoid having the body reject the stem cells but reduces the body’s overall defenses against any sort of infection.

Neuralstem hopes to begin the trial in September.
Posted by Community Admin on Aug 22, 2014 12:33 PM America/New_York

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