Regenerating Nerve Tissue in Spinal Cord Injuries


Severe injuries to the neck during recreational activities such as horseback riding or playing football can permanently alter someone’s life dramatically. With no options for the repair of spinal cord injuries, many are left with little hope for recovery.

New work by researchers at Rush University Medical Center (RUMC) in Chicago is investigating a new therapy that uses stem cells to treat spinal cord injuries within the first 14 to 30 days of injury. Rush is one of only two centers in the country currently studying this new approach.

“There are currently no therapies that successfully reverse the damage seen in the more than 12,000 individuals who suffer a spinal cord injury each year in the United States alone,” says Richard G. Fessler, MD, PhD, professor of neurological surgery at RUMC. An estimated 1.3 million Americans are living with a spinal cord injury.

“These injuries can be devastating, causing both emotional and physical distress, but there is now hope. This is a new era where we are now able to test whether a dose of stem cells delivered directly to the injured site can have an impact on motor or sensory function,” Fessler continued. “If we could generate even modest improvements in motor or sensory function, it would result in significant improvements in quality of life.”

Dr. Fessler is the principal investigator at RUMC of a clinical trial that involves progenitor cells that are likely to develop into a certain cell types. Specifically, this study is studying nerve cells known as oligodendrocyte progenitor cells, which potentially can make poorly functioning nerves function better. A San Francisco Bay-area biotechnology company known as Asterias Biotherapeutics, developed the cells and is sponsoring the trial.

This clinical trial is designed to assess the safety and efficacy of increasing doses of AST-OPC1 to treat individuals with a cervical spinal cord injury that resulted in tetraplegia, the partial or total paralysis of arms, legs and torso. As of mid-August, one individual has been enrolled in the study at Rush and there are high hopes that others will be enrolled as well in the near future.

Three escalating doses of AST-OPC1 will be examined in patients with subacute, neurologically complete injury to the cervical spinal cord (the spinal cord in the neck, specifically, the spinal nerves known as C5 to C7). These individuals essentially have lost all sensation and movement below their injury site and have severe paralysis of the upper and lower limbs.

In order for this therapy to work, the spinal cord must be continuous not severed. Patients must be able to begin treatment within 25 days of their injury.

Fessler and his group will administer AST-OPC1 between 14 to 30 days after sustaining the injury. Following the treatment, patients will receive frequent neurological exams and imaging in order to assess the efficacy of the treatment. Furthermore, patients will be followed for 15 years thereafter.

“If this treatment proves to be safe and effective, in the future, it also might be used for peripheral nerve injury or other conditions that affect the spinal cord, such as multiple sclerosis or ALS,” Fessler says.

The study is recruiting male and female patients ages 18 to 65 who have recently experienced a cervical spinal cord injury at the neck that resulted in partial or total paralysis of arms, legs and torso. All participants must be able to provide consent and commit to a long-term follow-up study.

Using Drugs to Stimulate your Own Stem Cells to Treat Multiple Sclerosis


Paul Tesar from Case Western Reserve in Cleveland. Ohio and his colleagues have discovered that two different drugs, miconazole and clobetasol, can reverse the symptoms of multiple sclerosis in laboratory animals. Furthermore, these drugs do so by stimulating the animals’ own native stem cell population that insulates nerves.

Multiple sclerosis (MS) is a member of the “demyelinating disorders.” The cause of MS remains unknown, but all of our available evidence strongly suggests that MS is an autoimmune disease in which the body’s immune system attacks its own tissues. In MS the immune system attacks and destroys myelin — the fatty substance that coats and protects nerve fibers in the brain and spinal cord. We can compare myelin to the insulation that surrounds electrical wires. When myelin is damaged, the nerve impulses that travel along that nerve may be slowed or blocked.

The myelin sheath is made by cells known as “oligodendrocytes,” and oligodendrocytes are derived from a stem cell population known as OPCs, which stands for oligodendrocyte progenitor cells. If this stem cell population could be stimulated, then perhaps the damaged myelin sheath could be repaired and the symptoms of MS ameliorated.

In a paper that appeared in the journal Nature (522, 2015 216-220), Tesar and the members of his research team, and his collaborators used a pluripotent mouse stem cell line and differentiated them into OPCs. Thyroid hormone is a known inducer of OPC differentiation. Therefore, Tesar and others screened a battery of drugs to determine if any of these compounds could induce OPC differentiation as cell as thyroid hormone. From this screen using cultured OPCs, two drugs, the antifungal drug miconazole and clobetasol, a corticosteroid of the glucocorticoid class, proved to do a better job of inducing OPC differentiation than thyroid hormone.

Was this an experimental artifact? Tesar and others devised an ingenious assay to measure the effectiveness of these two drugs. They used brain slices from fetal mice that were taken from animals whose brains had yet to synthesize myelin and applied OPCs to these slices with and without the drugs. With OPCs, no myelin was made because the OPCs did not receive any signal to differentiate into mature oligodendrocytes and synthesize myelin. However in the presence of either miconazole or clobetasol, the OPCs differentiated and successfully myelinated the brain slices.

Experiments in tissue culture are a great start, but do they demonstrate a biological reality within a live animal? To answer this question, Tesar and his crew injected laboratory mice with purified myelin. The immune systems of these mice generated a robust immune response against myelin that eroded the myelin sheath from their nerves. This condition mimics human MS and is called experimental autoimmune encephalitis, and it is an excellent model system for studying MS. When mice with experimental autoimmune encephalitis (EAE) were treated with either miconazole or clobetasol, the EAE mice showed a remarkable reversal of symptoms and a solid attenuation of demyelination. Tissue samples established that these reversals were due to increased OPC activity.

When the mechanisms of these drugs were examined in detail, it became clear that the two drugs worked through distinct biochemical mechanisms. Miconazole, for example, activated the mitogen-activated protein kinase (MAPK) pathway, but clobetasol worked through the glucocorticoid receptor signaling pathway. Both of these signaling pathways converge, however, to increase OPC differentiation.

Both miconazole and clobetasol are only approved for topical administration. However, the fact that these drugs can cross the blood-brain barrier and effect changes in the brain is very exciting. Furthermore, this work establishes the template for screening new compounds that might be efficacious in human patients.

In the meantime, human patients might benefit from a clinical trial that determines if the symptoms and neural damage caused by MS can be reversed by the administration of these drugs or derivatives of these drugs.

Human Stem Cells Repair Radiation Damage in Rat Brains


Radiation is a powerful treatment for brain cancer, but this potentially life-saving treatment comes with a heavy cost, which is permanent damage to the brain.

Preclinical work at Memorial Sloan Kettering Cancer Center has shown that human stem cells can be used to make cells that repair radiation-induced damage in the brain.

When rats were treated with radiation and then given cocktails to the human stem cells, they regained the cognitive and motor functions that were lost after brain irradiation.

In the brain, stem cells called OPCs or oligodendrocyte progenitor cells mature into oligodendrocytes that produce the protective myelin coating that surrounds axons in the central nervous system. During radiation treatment, OPCs die off and are depleted. Because OPCs help shield and repair the myelin sheath throughout the life of the organism, depletion of them threatens the integrity of the myelin sheath, which threatens the proper transmission of neural impulses throughout the brain.

A research project led by neurosurgeon Viviane Tabar and her research associate Jinghua Piao wanted to use stem cells to replace these lost OPCs. They used human embryonic stem cells and human induced pluripotent stem cells to make cultured OPCs.

In the next phase of the experiment, Taba, Piao and their coworkers treated rats whose brains had been irradiated with their cultured OPCs. After injection of the stem cell-derived OPCs, brain repair was evident and the rats regained their cognitive and motor function that they had previously lost as a consequence of radiation exposure.

The treatment appeared quite safe since none of the animals developed any tumors or aberrant growths.

The ability to repair radiation damage could mean that the quality of cancer survivors could be greatly improved and it could also expand the therapeutic window of radiation, according to Tabor.

“This will have to be proven further, but if we can repair the brain effectively, we could be bolder with our radiation dosing, within limits,” said Tabor.

Such a treatment scheme could also be very important in children, for whom physicians must use lower doses of radiation to limit brain damage.

One Step Closer To Stem Cell Treatment for Multiple Sclerosis


Valentina Fossati and her colleague Panagiotis Douvaras from the New York Stem Cell Foundation (NYSCF) Research Institute have brought us one step closer to creating a viable stem cell-based therapy for multiple sclerosis from a patient’s own cells.

Valentina Fossati, Ph.D.
Valentina Fossati, Ph.D.

NYSCF scientists have, for the first time, produced induced pluripotent stem cell (iPSCs) lines from skin samples of patients who suffer from primary progressive multiple sclerosis. Fossati, Douvaras and colleagues also developed an accelerated protocol to differentiate iPSCs into oligodendrocytes, which are the myelin-making cells that insulate axons of central nervous system neurons. Destruction of the insulating myelin sheath is one of the hallmarks of multiple sclerosis, and oligodendrocyte progenitor cells or OPCs can replace damaged myelin sheath material.

Previously, producing oligodendrocytes from pluripotent stem cells required almost half a year to produce, which limited research on these cells and the development of treatments. This present study, however, has reduced the time required to make oligodendrocytes by half. This increases the feasibility of making these cells and using them in research and, potentially, for treatments.

Oligodendrocytes

By making oligodendrocytes from multiple sclerosis patients, researchers can use these cells to observe, in a culture dish, how multiple sclerosis develops and progresses. The improved protocol for deriving oligodendrocytes from iPSCs will also provide a platform for disease modeling, drug screening, and for replacing the damaged cells in the brain with healthy cells generated using this method.

“We are so close to finding new treatments and even cures for MS. The enhanced ability to derive the cells implicated in the disease will undoubtedly accelerate research for MS and many other diseases” said Susan L. Solomon, NYSCF Chief Executive Officer.

Valentina Fossati, NYSCF – Helmsley Investigator and senior author on the paper, said, “We believe that this protocol will help the MS field and the larger scientific community to better understand human oligodendrocyte biology and the process of myelination. This is the first step towards very exciting studies: the ability to generate human oligodendrocytes in large amounts will serve as an unprecedented tool for developing remyelinating strategies and the study of patient-specific cells may shed light on intrinsic pathogenic mechanisms that lead to progressive MS.”

NYSCF scientists established in this study that their improved the protocol for making myelin-forming cells worked and that the oligodendrocytes derived from the skin of these patients are functional, and able to form their own myelin when put into a mouse model. This is a definite step towards developing future autologous cell transplantation therapies in multiple sclerosis patients. These results also present new research venues to study multiple sclerosis and other diseases, since oligodendrocytes are implicated in many disorders. Therefore, Fossati and others have not only moved multiple sclerosis research forward, but also research on all demyelinating and central nervous system disorders.

“Oligodendrocytes are increasingly recognized as having an absolutely essential role in the function of the normal nervous system, as well as in the setting of neurodegenerative diseases, such as multiple sclerosis. The new work from the NYSCF Research Institute will help to improve our understanding of these important cells. In addition, being able to generate large numbers of patient-specific oligodendrocytes will support both cell transplantation therapeutics for demyelinating diseases and the identification of new classes of drugs to treat such disorders,” said Dr. Lee Rubin, NYSCF Scientific Advisor and Director of Translational Medicine at the Harvard Stem Cell Institute.

Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system, distinguished by recurrent episodes of demyelination and the consequent neurological symptoms. Primary progressive multiple sclerosis is the most severe form of multiple sclerosis, characterized by a steady neurological decline from the onset of the disease. Currently, there are no effective treatments or cures for primary progressive multiple sclerosis and treatments rely merely on symptom management.