Human Stem Cell-Derived Neurons Grow New Axons In Spinal Cord Injured Rats


A stem cell-based treatment for spinal cord injury took one more baby step forward when scientists from the laboratory of Mark Tuszynski at the at the University of California, San Diego used cells derived from an elderly man’s skin to regrow neural connections in rats with damaged spinal cords.

Tuszynski and others published their results in the Aug. 7 online issue of the journal Neuron. In that paper, Tuszynski and his co-worker report that human stem cells triggered the growth of numerous axons in the damaged spinal cord. Axons are those fibers that extend from the main part or body a neuron (nerve cell) that serve to send electrical impulses away from the body to other cells. Some of these new axons even grew into the animals’ brains.

Axon picture

Dr. Mark Tuszynski is a professor of neurosciences at the University of California, San Diego. “This degree of growth in axons has not been appreciated before,” he said. However, Tuszynski also cautioned that there is still much to be learned about how these newly established nerve fibers behave in laboratory animals. He likened the potential for stem-cell-induced axon growth to nuclear fusion. If it’s contained, you get energy; if it’s not contained, you get an explosion. “Too much axon growth into the wrong places would be a bad thing,” Tuszynski added.

Stem cell researchers have examined the potential for stem cells to restore functioning nerve connections in people with spinal cord injuries. Embryonic stem cells have been used to make new neurons and to also make “oligodendrocyte progenitor cells” or OPCs, which make the insulating myelin sheath that enwraps the axons of spinal nerves. However, several other types of stem cells can make OPCs and new neurons and these stem cells do not come from embryos (for more, see chapter 27 of my book, The Stem Cell Epistles).

In this study, Tuszynski and his team used induced pluripotent stem cells or iPSCs, which are derived from mature adult cells by means of genetic engineering and cell culture techniques. They used cells from a healthy 86-year-old man and genetically reprogrammed so that they were reprogrammed into iPSCs. These iPSCs were then differentiated into neurons that were implanted into a special scaffold embedded with proteins called growth factors, and then grafted into the spinal cords of laboratory rats with spinal cord injuries.

Over the course of several months, these animals showed new, mature neurons and extensive growth in the cells’ axons. These fibers grew through the injury-related scar tissue in the animals’ spinal cords and connected with resident rat neurons.

This is an enormous advance, because the wounded spinal cord creates a “Glial scar” that contains a host of molecules that repel growing axons. Even though this glial scar prevents the immune system from leaking into the spinal cord and destroying it, this same scar prevents the regeneration of damaged neurons and their severed axons.

Glial scar axon repulsion

Dr. David Langer, director of neurosurgery at Lenox Hill Hospital in New York City said: “One of the big obstacles [in this type of research] is this area of scarring in the spinal cord. Getting neurons to traverse it is a real challenge,” said Langer, who was not involved in the research. “The beauty of this study,” he said, “is that they got the neurons to survive and traverse the scar.”

Langer also cautioned, much like Tuszynski, that this experimental success is just a preliminary step. There are, in his words, “huge questions” as to whether or not these axons can make appropriate connections and actually restore function to spine-damaged lab animals. “It’s not just a matter of having the cables,” Langer said. “The wiring has to work.”

And even if this stem cell approach does pan out in animals, Langer added, it would all have to be translated to humans. “We have a long way to go until we’re there,” he said. “It’s not that people shouldn’t have hope. But it should be a realistic hope.”

A few biotech companies have already launched early-stage clinical trials using embryonic (Geron) or fetal stem cells (StemCells Inc) to treat patients with spinal cord injuries. But Tuszynski said his team’s findings offer a cautionary note about moving to human trials too quickly. “We still have a lot to learn,” he said. “We want to be very sure these axons don’t make inappropriate connections. And we need to see if the new connections formed by these axons are stable.”

Ideally, Tuszynski added, if stem cells were to be used in treating spinal cord injuries, they’d be generated as they were in this study — by creating them from a patient’s own cells. That way, he explained, patients would not need immune-suppressing drugs afterward.

Tiny, Poorly-Controlled Study Shows No Benefit for Stem Cell Treatment in Children with Optic Nerve Hypoplasia


Optic nerve hypoplasia (ONH), an underdevelopment of optic nerves that occurs during fetal development, can appear as an isolated condition or as a part of a group of disorders characterized by brain anomalies, developmental delay, and endocrine abnormalities. ONH is a leading cause of blindness in children in North America and Europe and is the only cause of childhood blindness that shows increasing prevalence. No treatments have been shown to improve vision in these children.

RetinaRetina ONH

Because stem cells heal or even regenerate some tissues, some have considered stem cell treatments as an option for this condition.  However, a very small clinical study at Children’s Hospital Los Angeles found no evidence that stem cell therapies improve vision for children with optic nerve hypoplasia (ONH). Their results are reported in the Journal of the American Association for Pediatric Ophthalmology and Strabismus (AAPOS).

Families with a child that has ONH are traveling to China to undergo stem cell treatments that would be illegal in the United States. Because there are presently no viable treatment options available to improve vision in ONH children, such trips are often an act of desperation. The American Association for Pediatric Ophthalmology and Strabismus has also expressed its concern about these procedures, which are usually rather expensive, and have a dubious safety record.

Pediatric neuro-ophthalmologist Mark Borchert, MD, director of both the Eye Birth Defects and Eye Technology Institutes in The Vision Center at Children’s Hospital Los Angeles, realized that a controlled trial of sufficient size was needed to evaluate whether stem cell therapy is effective as a treatment for children with ONH. He agreed to conduct an independent study at the behest of Beike Biotech, which is based in Shenzhen, China and offers a stem cell treatment for ONH. This treatment uses donor umbilical cord stem cells and injects these cells into the cerebrospinal fluid.

Beike Biotech identified 10 children with bilateral ONH (ages 7 to 17 years) who had volunteered to travel to China for stem cell therapy. These patients gave their consent to participate in the study and Children’s Hospital found matched controls from their clinic. However, only two case-controlled pairs were evaluated because Beike Biotech was only able to recruit two patients.

Treatments consisted of six infusions over a 16-day period of umbilical cord-derived mesenchymal stem cells and daily infusions of growth factors. Visual acuity, optic nerve size, and sensitivity to light were to be evaluated one month before stem cell therapy and three and nine months after treatment.

Unfortunately no therapeutic effect was found in the two case-control pairs that were enrolled. “The results of this study show that children greater than 7 years of age with ONH may have spontaneous improvement in vision from one examination to the next. This improvement occurs equally in children regardless of whether or not they received treatment. Other aspects of the eye examination included pupil responses to light and optic nerve size; these did not change following treatment. The results of this research do not support the use of stem cells in the treatment of ONH at this time,” said lead author Cassandra Fink, MPH, program administrator at The Vision Center, Children’s Hospital Los Angeles.

However, confounding factors affect the interpretation of these results because the test subjects received additional alternative therapies (acupuncture, functional electrical stimulation and exercise) while receiving stem cell treatments. They were not supposed to receive such treatments. Additionally, the investigators could not determine the effect of these additional therapies on the subjects’ eyes.

“This study underscores the importance of scientifically testing these procedures to validate them and ensure their safety. Parents of afflicted children should be aware that the science behind the use of stem cell technology is unclear. This study takes a step toward testing this technology and finds no beneficial effect,” said William V. Good, MD, senior associate editor, Journal of AAPOS and Clinical Professor of Ophthalmology and Senior Scientist at the Smith-Kettlewell Eye Research Institute.

Basically, we have an incredibly small study that is also poorly controlled. Because the optic nerve forms during embryonic, fetal and postnatal development, using stem cells to make new nerves seems like a long shot as a treatment.  I better treatment strategy might be to increase the myelination of the optic nerve with neural stem cells, oligodendrocyte precursor cells (OPCs), or Schwann cells.  In general, this study does little to establish the lack of efficacy of such a stem cell treatment.

GERON’S IND FOR SPINAL CORD INJURY PLACED ON HOLD


Geron Corporation has made a cell line called GRNOPC1 from embryonic stem cells. GRNOPC1 is an “oligodendrocyte precursor cell” or OPC line. Before you blow a gasket at the sight of such a long-winded description, just remember that nerves are like wires and wires need insulation.  OPCs are the cells that make the insulation.  During spinal cord injury, the insulation dies off and it causes nerves to malfunction.

In collaboration with Hans Keirstead at UC Irvine, Geron developed a protocol for the administration of GRNOPC1 cells to animals with acute spinal cord injuries. His protocol showed that the OPCs were safe (no tumors were seen, even after one year) and somewhat effective. Some scientists were skeptical, since the mice had somewhat less severe spinal cord injuries.  Nevertheless, Geron was granted an Investigational New Drug Application from the FDA to conduct a Phase I trial with their OPC cell line.

They apparently, however, have bit a bit of a snag. Here is a press release from Geron Corporation.

Geron Corporation today announced that its IND (Investigational New Drug application) for GRNOPC1, a cell therapy for neurologically complete, subacute spinal cord injury, has been placed on clinical hold by the FDA pending the agency’s review of new nonclinical animal study data submitted by the company. A clinical hold is an order that the FDA issues to a sponsor to delay a proposed trial or to suspend an ongoing trial.

Since filing the IND, Geron has been undertaking studies to enable dose escalation of its spinal cord injury product, and has been investigating application of the product to other neurodegenerative diseases. The company has also been performing additional product characterization and conducting further animal studies. Data from this work has been submitted to the FDA. Geron will work closely with the FDA to facilitate their review of the new data and to release the clinical hold. No patients have yet been treated in this study.

From the sound of it, this hold is merely an administrative procedure that the FDA routinely undergoes when presented with new data.  However, if the new data is completely consonant with previous findings, why would there be a hold? We simply do not know at this time.  It is entirely possible that nothing is amiss, and this is merely FDA policy.  However, it is also possible that Geron’s new product does not behave exactly as they thought.

The development of the first cholesterol-lowering drug (lovastatin) experienced a slow-down when a related product being developed in Japan caused cancer in dogs. Roy Vagelos, president of Merck at the time, contacted the FDA and suspended all clinical trials. Further testing by Merck showed that this was an anomaly, and extensive clinical use has vindicated this finding. Maybe this is a similar situation for Geron’s OPC line?  Only time will tell.