Stem Cell Treatments Cure Mice With MS-Like Disease


University of California researchers have discovered that human stem cells can reverse a multiple sclerosis-type condition in mice. Soon to be published in the journal Stem Cell Reports, this work could potentially lead to new treatments for multiple sclerosis (MS).

When this team first transplanted the stem cells into severely disabled MS mice, they were quite sure that the immune systems of the mice would attack these transplanted stem cells, which were from humans, would attack and reject them. However, the experiment had surprising results.

“My postdoctoral fellow Dr. Lu Chen came to me and said, ‘The mice are walking.’ I didn’t believe her,” said co-senior author, Tom Lane, PhD., who is presently a professor of pathology at the University of Utah, who began this study at University of California, Irvine.

Within next 10 to 14 days, the mice regained their lost motor skills, and six months later, they still show no signs of slowing down.

“This result opens up a whole new area of research for us,” said co-senior author Jeanne Loring, PhD, a professor at The Scripps Research Institute in La Jolla, Calif.

A chronic disease, MS results from the body’s own immune system attacks the body’s central nervous system. In particular, the insulating layer that surrounds many nerve fibers – a fatty substance called myelin – is slowly destroyed and this exposes nerves and slows or interrupts the transmission of nerve impulses. The symptoms of MS may be mild or severe, and includes numbness in the limbs, difficulty walking, paralysis, loss of vision, fatigue and pain.

Researchers say the MS mice treated with human stem cells experienced a dramatic reversal of symptoms within days. Immune attacks were blunted and damaged myelin was repaired.

Chen, Loring and their colleagues were further surprised that not only did the mice not initially reject these implanted stem cells, but they never showed any signs of rejection, even after one week.

Now Lane and others are eager to test this therapy in human clinical trials.

“Rather than having to engraft stem cells into a patient, which can be challenging, we might be able to put those chemical signals into a drug that can be used to deliver the therapy much more easily,” said Lane. He continued: “I would love to see something that could promote repair and ease the burden that patients with MS have.”

Previous work with stem cells has shown some promise in the treatment of MS. For example, in 2013, the US Food and Drug Administration (FDA) approved a small clinical trial of genetically modified mesenchymal stem cells initially harvested from bone marrow of MS patients. These stem cells were injected into the cerebrospinal fluid that surrounds the spinal cords of MS patients. Previous small studies conducted between 2005 and 2007 of this therapy in humans found that implantation of these modified stem cells reduced brain inflammation and repaired damaged layers of myelin. This small study only treated and tested seven patients.

There is no known cure for MS and drugs to treat it have limited effectiveness. An estimated 400,000 Americans have the disease and more than 2 million worldwide.

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.