Autologous Stem Cell Transplantation With Complete Ablation of Bone Marrow Delays Progression of Multiple Sclerosis in Small Phase 2 Trial


Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Around 2 million people, worldwide, suffer from MS. MS results from the patient’s immune system attacking the myelin sheath that surrounds nerve axons. These constant and relentless attacks upon the myelin sheath causes “demyelination,” resulting in loss of the sensory and motor function.

Treatment usually required the use of drugs that suppress the immune response. Some of these drugs work better than others, while other patients have forms of MS that do not respond to common MS treatment.

A new report published in the Lancet, has shown that chemotherapy followed by autologous hematopoietic stem cell transplantation (aHSCT) can completely halt clinical relapses of MS and prevent the development of new brain lesions in 23 of 24 MS patients. Patients who participated in this study experienced a prolonged period without the need for ongoing medication. Eight of the 23 patients had a sustained improvement in their disability 7.5 years after treatment. This is the first treatment to produce this level of disease control or neurological recovery from MS, but, unfortunately, treatment related risks limit its widespread use.

There are a few specialist centers that offer MS patients aHSCT. This treatment involves harvesting bone marrow stem cells from the patient, and then employing chemotherapy to suppress the patient’s immune system and essentially partially wipe it out. The isolated bone marrow is then reintroduced into the blood stream to “reset” the immune system and stop it attacking the body. However, a respectable percentage of MS patients relapse after these treatments. Therefore, these treatments must be refined and tweaked to improve their efficacy.

Drs Harold L Atkins and Mark S Freedman from The Ottawa Hospital and the University of Ottawa, Ottawa, Canada, respectively, and their colleagues, tested if complete destruction, rather than suppression, of the immune system during aHSCT could reduce the relapse rate in patients and increase the long-term rates of disease remission. They enrolled 24 patients aged 18-50 from three Canadian hospitals. All of these subjects had previously undergone standard immunosuppressive therapy, but these treatments had failed to control their MS. These patients all had poor prognosis and their disability ranged from moderate to requiring a walking aid to walk 100 meters (according to their Expanded Disability Status Scale or EDSS score).

Adkins and Freeman and their coworkers used a chemotherapy regimen of busulfan, cyclophosphamide and rabbit anti-thymocyte globulin to wipe out the patient’s bone marrow. Atkins explained that this treatment is “similar to that used in other trials, except our protocol uses stronger chemotherapy and removes immune cells from the stem cell graft product. The chemotherapy we use is very effective at crossing the blood-brain barrier and this could help eliminate the damaging immune cells from the central nervous system.” After being treated with chemotherapy regimen, the patients’ bone marrow was reconstituted with their previously isolated bone marrow.

This study’s primary outcome was activity-free survival at 3 years, using EDSS scores as the means of measuring MS progression, in addition to scanning for brain lesions, and assessing MS symptoms.

Of the 24 patients enrolled, one (4%) died from liver failure and sepsis caused by the chemotherapy. In the 23 surviving patients, prior to treatment, patients experienced 1.2 relapses per year on average, but after aHSCT, no relapses occurred during the follow-up period (between 4 and 13 years). These clinical outcomes were nicely complemented by an absence of newly detected brain lesions (as assessed by MRI images taken after the treatment). Initially, 24 MRI scans of the brains of all 24 subjects revealed 93 brain lesions, and after the treatment only one of the 327 scans showed a new lesion.

Despite the exciting success of this clinical trial, Freedman emphasized the need to interpret these results with caution: “The sample size of 24 patients is very small, and no control group was used for comparison with the treatment group. Larger clinical trials will be important to confirm these results. Since this is an aggressive treatment, the potential benefits should be weighed against the risks of serious complications associated with aHSCT, and this treatment should only be offered in specialist centers experienced both in multiple sclerosis treatment and stem cell therapy, or as part of a clinical trial. Future research will be directed at reducing the risks of this treatment as well as understanding which patients would best benefit from the treatment.”

Dr Jan Dörr, from the NeuroCure Clinical Research Center, Charité-Universitätsmedizin, Berlin, Germany, made this comment about this clinical trial: “These results are impressive and seem to outbalance any other available treatment for multiple sclerosis. This trial is the first to show complete suppression of any inflammatory disease activity in every patient for a long period…However, aHSCT has a poor safety profile, especially with regards to treatment-related mortality.”

He added: “So, will this study change our approach to treatment of multiple sclerosis? Probably not in the short-term, mainly because the mortality rate will still be considered unacceptably high. Over the longer term (and) in view of the increasing popularity of using early aggressive treatment, there may be support for considering aHSCT less as a rescue therapy and more as a general treatment option, provided the different protocols are harmonized and optimized, the tolerability and safety profile can be further improved, and prognostic markers become available to identify patients at risk of poor prognosis in whom a potentially more hazardous treatment might be justified.”

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.

MS Patients in Phase 1 Stem Cell Trial Show Improvement


Phase 1 clinical studies are designed to determine the proper dosage of an agent and to assess the safety of a drug. Phase 1 studies are not designed to determine if the patients who take the drug or agent benefit from it. Therefore, it is highly gratifying to see a medical agent produce distinct improvements in a phase 1 study.

The Tisch MS Research Center of New York (Tisch MSRCNY) has announced in an April 23rd press release that patients enrolled in their FDA-approved Phase I trial using autologous neural stem cells in the treatment of multiple sclerosis (MS) show significant improvements. These results were presented during the Multiple Sclerosis Highlights in the Field session at the 67th American Academy of Neurology (AAN) Annual Meeting in Washington, D.C.

MS is a chronic autoimmune disease of the central nervous system caused by attacks against the myelin sheath by the patient’s own immune system. The destruction of the myelin sheath causes systemic neurodegeneration. MS affects more than 2.3 million people worldwide.

In its interim analysis of their data, Tisch MSRCNY researchers reported that six of the nine patients treated with stem cells show increased motor strength, improved bladder function and an enhanced quality of life. Significantly, these treatments are well tolerated and, to date, no serious adverse events were reported.

“This preliminary data is encouraging because in addition to helping establish safety and tolerability, the trial is yielding some positive therapeutic results even at this early stage,” said Dr. Saud A. Sadiq, Chief Research Scientist at Tisch MSRCNY and the study’s principal investigator. Sadiq cautioned that these results result from an interim analysis and definitive conclusions will only be made upon completion of the trial.

The Tisch MSRCNY study investigates a pioneering regenerative strategy that utilizes stem cells harvested from the patient’s own bone marrow.  Specifically, a special stem cell population called “MSC-NPs” or mesenchymal stem cell-derived neural progenitors are isolated from bone marrow and used in this clinical trial.  MSC-NPs represent a neural subpopulation of bone marrow-derived MSCs with reduced mesodermal pluripotency and minimized risk of ectopic differentiation.  In preclinical studies in laboratory mice afflicted with “experimental autoimmune encephalomyelitis” (an excellent model system for MS), Tisch MSRCNY scientists established that three doses of MSC-NPs delivered intrathecally (IT) resulted in improved neurological function associated with suppression of local inflammatory response and trophic support for damaged cells at lesion sites.

Once the MSC-NPs were isolated from the patient’s bone marrow stem cell, they were injected intrathecally, that is, into the cerebrospinal fluid surrounding the spinal cord, in 20 participants who meet the inclusion criteria for the trial. This is an open label safety and tolerability study, which means that both the physicians and patients know what treatments that are giving and receiving in contrast to blinded studies. All clinical activities in this study will be are conducted at Tisch MS Research Center of New York or at affiliated International Multiple Sclerosis Management Practiced. The interim analysis reports on the first nine patients who received at least one treatment of stem cells.

Study patient Vicky Gill, a married mother of two whose husband, Michael, also has MS, has already experienced the positive benefits of the therapy. “For the past six years, I would fall frequently, had very limited movement in my legs and always walked with my cane. After just two stem cell treatments, I am now gaining sensation and function I thought was totally lost, have not had any recent falls and at times don’t need a cane at all.”

The patients in this trial will receive three rounds of injections at three-month intervals. Safety and efficacy parameters will be evaluated in all patients through regular follow-up visits. Dr. Sadiq plans to continue and complete the Phase I study and if these positive trends continue, move on to a multi-center Phase II efficacy trial.

Bone Marrow Stem Cell Treatment Plus Immunosuppression are Superior to Immunosuppression Alone in Multiple Sclerosis Patients


Multiple Sclerosis (MS) is a debilitating autoimmune disease in which the immune system attacks elements of the central nervous system. There are different types of MS, but more progressive cases can leave patients unable to walk and may require rather extreme immunosuppressive treatments that can predispose a patient to illness and cancer.

However, a new study that was published in the journal Neurology has shown that stem cell transplantation could be a more effective therapy in severe cases of multiple sclerosis (MS) than the drug mitoxantrone.

Mitoxanthone is a “type II topoisomerase inhibitor” that disrupts DNA synthesis and DNA repair by inserting between the bases in DNA. Mitoxanthone can cause nausea, vomiting, hair loss, heart damage, and suppression of the immune system. Some side effects may have delayed onset. Heart damage (cardiomyopathy) is a particularly concerning effect with this drug, since it is irreversible. Therefore, because of the risk of cardiomyopathy, mitoxantrone carries a limit on the cumulative lifetime dose, which is based on the body surface area of patients.

Mitoxantrone
Mitoxantrone

Because MS is an immune-mediated disorder, and because immune cells are made by stem cells in the bone marrow, bone marrow transplants (hematopoietic stem cell transplantation), which are routinely used in the treatment of leukemia and lymphoma, are being considered as a treatment for MS.

A clinical trial conducted by Giovanni Mancardi from the University of Genova, Italy designed a randomized phase II clinical trial study that included 21 MS patients, whose average age was 36 and whose disability due to the disease had worsened in the previous year despite the fact that the patients were under conventional medication treatment. The average disability level of the participants was represented by the need of a crutch or cane to walk. The goal of the study was to determine the efficacy of intense immunosuppression followed by either a bone marrow transplant with the patient’s own bone marrow, or mitoxantrone (MTX) in MS disease activity.

Giovanni Mancardi
Giovanni Mancardi

All participants in this clinical trial received immune-suppressive medication. MTX was given to 12 of the patients while the remaining 9 received hematopoietic stem cells harvested from their own bone marrow. After treatment with MTX, the stem cells were intravenously reintroduced into their donors and the stem cells migrated back to the bone marrow where they generated new immune cells. All participants were followed-up for a period of up to four years after their treatment.

“This process appears to reset the immune system,” said the lead study author Dr. Giovanni Mancardi. “With these results, we can speculate that stem cell treatment may profoundly affect the course of the disease.”

Mancardi and his team found that treatment of MS patients with robust immunosuppression followed by stem cell treatment resulted in a significantly higher decrease in disease progression in comparison with MTX treatment alone. MS patients under stem cell treatment reduced the number of new areas of brain damage (T2 lesions) by 79% compared to patients under MTX treatment. Another type of lesion seen in MS patients – gadolinium-enhancing lesions – were not detected in patients under stem cell treatment during the study, whereas 56% of patients receiving MTX exhibited at least one new gadolinium-enhancing lesion.

Mancardi and his team concluded that an intense immunosuppression followed by autologous hematopoietic stem cell transplantation is more efficient than MTX to reduce MS activity in severe cases.

“More research is needed with larger numbers of patients who are randomized to receive either the stem cell transplant or an approved therapy, but it’s very exciting to see that this treatment may be so superior to a current treatment for people with severe MS that is not responding well to standard treatments,” concluded study author Dr. Mancardi.

Cells from placentas safe for patients with multiple sclerosis


A new Phase I clinical trial has demonstrated that Multiple Sclerosis (MS) patients were able to safely tolerate treatment with cells cultured from human placental tissue.  The results of this study were recently published in the journal Multiple Sclerosis and Related Disorders.  This pioneering study was conducted by researchers at Mount Sinai, Celgene Cellular Therapeutics, which is a subsidiary of Celgene Corporation, and collaborators at several other institutions, including the Swedish Neuroscience Institute in Seattle, WA, MultiCare Health System-Neuroscience Center of Washington, London Health Sciences Centre at University Hospital in London, the Clinical Neuroscience Research Unit at the University of Minnesota, the University of Colorado Denver, The Ottawa Hospital Multiple Sclerosis Clinic, and the MS Comprehensive Care Center at SUNY.

Even though this clinical trial was designed solely to determine the safety of this treatment, the data collected from the participating patients suggested that a preparation of cultured cells called PDA-001 may repair damaged nerve tissues in patients with MS.  PDA-001 cells resemble “mesenchymal,” stromal stem cells, which are found in many tissues of the body.  However, in this study, the cells were grown in cell culture systems, which means that one donor was able to supply enough cells for several patients.

“This is the first time placenta-derived cells have been tested as a possible therapy for multiple sclerosis,” said Fred Lublin, MD, Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Professor of Neurology at Icahn School of Medicine at Mount Sinai and the lead investigator of the study. “The next step will be to study larger numbers of MS patients to assess efficacy of the cells, but we could be looking at a new frontier in treatment for the disease.”

MS is a chronic autoimmune disease.  The body’s immune system attacks the insulating myelin sheath that surrounds and protectively coats the nerve fibers in the central nervous system.  The myelin sheath greatly improves the speed at which nerve impulses pass through these nerves and without the myelin sheath, nerve impulse conduction becomes sluggish, and the nerves also eventually die off.  Long-term, MS causes extensive nerve malfunction and can lead to paralysis and blindness.  MS usually begins as an episodic condition called “relapsing-remitting MS” or RRMS.  Patients will have occasional outbreaks of nerve malfunction, pain, or numbness.  However, many MS patients will see their condition evolves into a chronic condition with worsening disability called “secondary progressive MS” or SPMS.

This Phase I trial examined 16 MS patients, 10 of whom had  RRMS and six of whom were diagnosed with SPMS and were between the ages of 18 and 65.  Six patients were given a high dose of the placental-based cell line PDA-001, and another six were given a lower dose.  The remaining four patients were given placebos.  Dr. Lubin noted that alteration of the immune system by any means can cause MS to worsen in some patients.  Therefore, all participating subjects were given monthly brain scans over a six-month period to ensure they did not acquire any new or enlarging brain lesions, which are indicative of worsening MS activity.  However, none of the subjects in this study showed any paradoxical worsening on MRI and after one year.  The majority had stable or improved levels of disability.

“We’re hoping to learn more about how placental stromal cells contribute to myelin repair,” said Dr. Lublin. “We suspect they either convert to a myelin making cell, or they enhance the environment of the area where the damage is to allow for natural repair. Our long-term goal is to develop strategies to facilitate repair of the damaged nervous system.”

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.

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.