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.

Spiking Stem Cells to Generate Myelin


Regenerating damaged nerve tissue represents a unique challenge for regenerative medicine. Nevertheless, some experiments have shown that it is possible to regenerate the myelin sheath that surrounds particular nerves.

Myelin is a fatty, insulating sheath that surrounds particular nerves and accelerates the transmission of nerve impulses. The myelin sheath also helps neurons survive, and the myelin sheath is attacked and removed in multiple sclerosis, a genetic disease called Charcot-Marie-Tooth disease, and spinal cord injuries. Being able to regenerate the myelin sheath is an essential goal of regenerative medicine.

Fortunately, a new study from a team of UC Davis (my alma mater) scientists have brought this goal one step closer. Wenbig Deng, principal investigator of this study and associate professor of biochemistry and molecular medicine, said, “Our findings represent an important conceptual advance in stem cell research. We have bioengineered the first generation of myelin-producing cells with superior regenerative capacity.”

The brain contains two main cell types; neurons and glial cells. Neurons make and transmit nerve impulses whereas glial cells support, nourish and protect neurons. One particular subtype of glial cells, oligodendrocytes, make the myelin sheath that surrounds the axons of many neurons. Deng and his group developed a novel protocol to induce embryonic stem cells (ESCs) to differentiate into oligodendrocyte precursor cells or OPCs. Even though other researchers have made oligodenrocytes from ESCs, Deng’s method results in purer populations of OPCs than any other available method.

Making OPCs from ESCs is one thing, but can these laboratory OPCs do everything native can do? When Deng and his team tested the electrophysiological properties of their laboratory-made OPCs, they discovered that their cells lacked an important component; they did not express sodium channels. When the lab-made OPCs were genetically engineered to express sodium channels, they generated the characteristic electrical spikes that are common to native OPCs. According to Deng, this is the first time anyone has made OPCs in the laboratory with spiking properties. Is this significant?

Deng and his colleagues compared the spiking OPCs to non-spiking OPCs in the laboratory. Not only did the spiking OPCs communicate with neurons, but they also did a better job of maturing into oligodentrocytes.

Transplantation of these two OPC populations into the spinal cord and brains of mice that are genetically unable to produce myelin also showed differences. Both types of OPCs were able to mature into oligodendrocytes and produce myelin sheaths, but only the spiking OPCs had the ability to produce longer and thicker myelin sheaths.

Said Deng, “We actually developed ‘super cells’ with an even greater capacity to spike than natural cells. This appears to give them an edge for maturing into oligodendrocytes and producing better myelin.

Human neural tissue has a poor capacity to regenerate and even though OPCs are present, they do not regenerate tissue effectively when disease or injury damages the myelin sheath. Deng believes that replacing glial cells with the enhanced spiking OPCs to treat injuries and diseases has the potential to be a better strategy than replacing neurons, since neurons are so problematic to work with in the laboratory. Instead providing the proper structure and environment for neurons to live might be the best approach to regenerate healthy neural tissue. Deng also said that many diverse conditions that have not been traditionally considered to be myelin-based diseases (schizophrenia, epilepsy, and amyotrophic lateral sclerosis) are actually now recognized to involve defective myelin.

On that one, I think Deng is dreaming. ALS is caused by the death of motor neurons due to mechanisms that are intrinsic to the neurons themselves. Giving them all the myelin in the world in not going to help them. Also, OPCs made from ESCs will be rejected out of hand by the immune system if they are used to regenerate myelin in the peripheral nervous system. The only hope is to keep them in the central nervous system, but even there, any immune response in the brain will be fatal to the OPCs. This needs to be tested with iPSCs before it can be considered for clinical purposes.

StemCells, Inc. Presents Two-Year Pelizaeus-Merzbacher Disease Data Suggesting Increased Myelination of Nerves


StemCells, Inc. has presented data of their two-year follow-up of patients with Pelizaeus-Merzbacher disease (PMD) who were treated with the Company’s proprietary HuCNS-SC cells. HuCNS-SC is a purified human neural stem cell line, and these neural stem cells can differentiate into a very wide variety of cell types of the nervous system, including different types of neurons and glial cells.

PMD is an inherited condition that involves the central nervous system. It is one of a group of genetic disorders called “leukodystrophies,” which all have in common degeneration of myelin. Myelin covers nerves and protects them, and promotes the efficient transmission of nerve impulses. PMD is caused by an inability to synthesize myelin (dysmyelination). Consequently, PMD individuals have impaired language and memory abilities, and poor coordination. Typically, motor skills are more severely affected than intellectual function; motor skills development tends to occur more slowly and usually stops in a person’s teens, followed by gradual deterioration.

Since PMD is an X-linked genetic disease, it is far more prevalent in males, and an estimated 1 in 200,000 to 500,000 males in the United States have PMD, but it rarely affects females.

Mutations in the PLP1 gene usually cause PMD. The PLP1 gene encodes proteolipid protein 1 and a modified version (isoform) of proteolipid protein 1, called DM20. Proteolipid protein 1 and DM20 are primarily in the central nervous system and are the main proteins found in myelin. The absence of proteolipid protein 1 and DM20 can cause dysmyelination, which impairs nervous system function and causes the signs and symptoms of Pelizaeus-Merzbacher disease.

In this trial, PMD patients were injected with HuCNS-SC cells. In this report, magnetic resonance imaging (MRI) studies were used to determine the amount of myelin that insulated particular nerves in the central nervous system. MRI examination of the patients revealed evidence of myelination that is more pronounced that what was seen in the one year post-transplantation exams. The gains in neurological function reported after one year were maintained, and there were no safety concerns.

Patients with PMD have insufficient myelin in the brain and their prognosis is very poor, usually resulting in progressive loss of neurological function and death. The neurological and MRI changes suggest a departure from the natural history of the disease and may represent signals of a positive clinical effect. These data were presented by Stephen Huhn, MD, FACS, FAAP, Vice President, CNS Clinical Research at StemCells, Inc., at the 2013 Pelizaeus-Merzbacher Disease Symposium and Health Fair being held at Nemours/Alfred I. duPont Children’s Hospital in Wilmington, Delaware.

“We are encouraged that the MRI data continue to indicate new and durable myelination related to the transplanted cells and that the data is even stronger after two years compared to one year,” said Dr. Huhn. “Even in the context of a small open-label study, these MRI results, measured at time points long after transplantation, make an even more convincing case that the HuCNS-SC cells are biologically active and that their effect is measurable, sustainable, and progressive. Our challenge now is to reach agreement with the FDA on how best to correlate changes in MRI with meaningful clinical benefit, as this will be a critical step in determining a viable registration pathway for PMD.”

The Company’s Phase I trial was conducted at the University of California, San Francisco, and enrolled four patients with “connatal” PMD, which is the most severe form of PMD. All four patients were transplanted with HuCNS-SC cells, and followed for twelve months after transplantation. During the year of post-transplantation observation, the patients underwent intensive neurological and MRI assessments at regular intervals. Since none of the patients experienced any serious or long-lasting side effects from the transplantation, the results of this Phase I trial indicate a favorable safety profile for the HuCNS-SC cells and the transplantation procedure.

Data from MRI analyses showed changes consistent with increased myelination in the region of the transplantation. This increased myelination progressed over time and persisted after the withdrawal of immunosuppressive drugs nine months after transplantation. These results support the conclusion of durable cell engraftment and donor cell-derived myelin in the transplanted patients’ brains. Also, routine neurological exams revealed small but consistent and measurable gains in motor and/or cognitive function in three of the four patients. The fourth patient remained clinically stable. These Phase I trial results were published in October 2012 in Science Translational Medicine, the peer review journal of the American Association for the Advancement of Science. Upon completion of the Phase I trial, all four patients were enrolled into a long-term follow-up study, which is designed to follow the patients for four more years.