New Analysis of Stem Cell Treatments for Spinal Cord Injury in Laboratory Animals


A host of preclinical studies have examined the ability of stem cells to improve the condition of laboratory animals that have suffered a spinal cord injury. While these studies vary in their size, design, and quality, there has been little cumulative analysis of the data generated by these studies.

Fortunately, there is a powerful analytical tool that can examine data from many studies and this type of analysis is called a “meta-analysis.” Meta-analyses use sophisticated statistical packages to systematically reassess a compilation of the data contained within these papers. Meta-analyses are exhausting, but potentially very useful. Such a meta-analysis is also very important because it provides researchers with an indication of what problems must be worked out before these treatments advance to human clinical trials and what aspects of the treatment work better than others.

A recent meta-analysis of stem cell therapy on animal models of spinal cord injury has been published by Ana Antonic, MSc, David Howells, Ph.D., and colleagues from the Florey Institute and the University of Melbourne, Australia, along with Malcolm MacLeod and colleagues from the University of Edinburgh, UK in the open access journal PLOS Biology.

The goal of regenerative spinal cord treatments is to use stem cells to replace dead cells within damaged areas of the spinal cord. Such treatments would be given to spinal cord injury patients in the hope of improving the ability to move and to feel below the site of the injury. Many experiments that utilize animal models of spinal cord injury have used stem cells to treat laboratory animals that have suffered spinal cord injury, but, unfortunately, these studies are limited in scale by size (as a result of financial considerations), practical and ethical considerations. Such limitations hamper each individual study’s statistical power to detect the true effects of the stem cell implantation. Also, these studies use different types of stem cells in their treatment scenarios, inject those cells differently induce spinal cord injuries differently, and test their animals for functional recovery differently.

To assess these studies, this new paper examined 156 published studies, all of which tested the effects of stem cell treatments on about 6,000 spinal cord-injured animals.

Overall, they found that stem cell treatment results in an average improvement of about 25 percent over the post-injury performance in both sensory (ability to feel) and motor (ability to move) outcomes. Unfortunately, the variation from one animal to another varied widely.

For sensory outcomes the degree of improvement tended to increase with the number of cells implanted. Such dose-responsive results tend to indicate that the improvements are actually due to the stem cells, and therefore, this stem cell-mediated effect represents a genuine biological effect.

The authors also measured the effects of bias. Simply put, if the experimenters knew which animals were treated and which were untreated, then they might be more likely to report improvements in the stem cell-treated animals. They also examined the way that the stem cells were cultured, the way that the spinal injury was generated and the way that outcomes were measured. In each case, important lessons were learned that should help inform and refine the design of future animal studies.

The meta-analysis also revealed some surprises that should provoke further investigations. For example, there was little evidence that female animals showed any beneficial sensory effects as a result of stem cell treatments. Also, the efficacy of the stem cell treatment seemed to not depend on whether immunosuppressive drugs were administered or not.

The authors conclude, “Extensive recent preclinical literature suggests that stem cell-based therapies may offer promise; however the impact of compromised internal validity and publication bias means that efficacy is likely to be somewhat lower than reported here.”

Even though human clinical trials are in the works, such trials will continue to be informed by preclinical studies on laboratory animals.

Stem Cell Trial for ALS Patients


Two patients afflicted with amyotrophic lateral sclerosis have received stem cell injections into their spinal cords at the University of Michigan Health System. These are the first two subjects in a national clinical trial.

Both of these volunteers have returned home and will continue to receive medical follow-up and monitoring in order to assess the safety of this procedure and to detect any potential improvements in the condition of these patients.

Additional patients with this condition, which is also known as Lou Gehring’s disease, are being evaluated for possible participation in the trial at U-M and Emory University. This phase 2 trial is approved by the US Food and Drug Administration (US FDA) and is being funded by a Maryland-based company called Neuralstem, Inc., the proprietor of this stem cell product.

Neuralstem, Inc., has developed a neural stem cell line called NSI-566. When injected into the central nervous system of a living animal, these cells will divide up to 60 times and differentiate into a variety of neural cells (neurons, glial cells, etc.). Several publications have shown that injected NSI-566 cells survive when injected into the spinal cord, differentiate into several different neural cell types, and successfully integrate into the presently existing neural network.

In ALS patients, motor neurons progressively die off in the spinal cord, which limits voluntary movement.  ALS is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord, leading to complete paralysis, and eventually, death. According to the ALS Association, as many as 30,000 Americans have the disease, and about 5,600 people in the U.S. are diagnosed with ALS each year.  The goal of this treatment strategy is to stabilize ALS patients and to replace dead or dying neurons and to slow the progressive decline and loss of movements, walking, and eventually breathing.

Eva Feldman, professor of neurology at the U-M Medical School, is the principal investigator for this clinical trial, and serves as an unpaid consultant to Neuralstem, Inc.  Dr. Feldman led the analysis of the results from the Phase 1 trial, which ended in 2012.  In this Phase 1 trial, 100,000 cells were delivered to each patient, and the patients tolerated them well and experienced to severe side effects.  One subgroup of patients seemed to experience interruption of the progression of ALS symptoms.

Feldman commented, “We’re going to be permitted to give more injections and more stem cells, in Phase 2.  We’re very excited that we have been able to bring this important work to the University of Michigan.”

Parag Patil, a neurosurgeon and biomedical engineer, performed both operations on the trial participants.  In each case, the patient’s spinal column was unroofed and the spinal cord exposed to receive the cells.  The stem cells are then introduced by means of a custom-designed delivery device that is affixed to the subject’s spinal bones so that it moves with the patient’s breathing throughout the process.

Neuralstem spinal cord injection device

Patil, as assistant professor, also serves as a paid engineering consultant to Neuralstem, Inc., in order to further prefect the injection device.  A third participant in this clinical trial received a stem cell injection in September at Emory University in Atlanta, Georgia.  This Phase 2 dose escalation trial is designed to treat up to 15 ambulatory patients in five different dosing cohorts, and will do so under an accelerated dosing and treatment schedule.  The first 12 patients will be divided into four cohorts and each will receive injections only in the cervical region of the spinal cord, where breathing function is controlled.

The first cohort of three patients received 10 cervical region injections of 200,000 stem cells per injection.  The trial will now progress to a maximum of 20 cervical injections of up to 400,000 stem cells per injection.  The last three Phase 2 patients will receive injections into the cervical and lumbar spinal regions, and will receive 20 injections of 400,000 cells in the lumbar region in addition to the cervical injections they have already received.  The trial also accelerates the treat schedule, and is designed to progress at the rate of one cohort per month with one month observations periods between cohorts.  Researchers expect all of the patients could be treated by the end of the second quarter in 2014.
Lumbar and Cervical