Autologous hematopoietic stem cell transplantation, also known as “stem cell therapy” or by the acronym aHSCT, is an emerging yet controversial treatment method for multiple sclerosis (MS).

How aHSCT works for treatment of multiple sclerosis

The first step in aHSCT for MS involves collecting stem cells extracted from the patient’s bone marrow, peripheral blood or umbilical cord blood. After the material is collected, the patient’s immune system is either partially or completely ablated (immunoablation), which means the immune system is significantly reduced or destroyed temporarily with combinations of chemotherapy, monoclonal antibodies, and anti-thymocyte globulin. Because multiple sclerosis is an autoimmune disease, immune system suppression is a key step to essentially “reprogramming” it to function properly.

After immunoablation is complete, the collected stem cells are then re-infused to reconstitute the immune system and re-activate it. The intended result of the therapy is to return the immune system to a functional state so that the body’s autoimmune attack on myelin is halted.

Clinical studies involving aHSCT for MS

Autologous hematopoietic stem cell transplantation, an experimental therapeutic approach for multiple sclerosis as well as other diseases, has been tested in clinical settings and reviewed by leading scientists. Below are consolidated reports on three prominent aHSCT studies.

The first study consists of a case series involving a mix of 151 participants with relapsing and progressive MS. All participants underwent the treatment at Northwestern University in Chicago from July 2003 to February 2014.

A significant proportion of the patients (63%) were treated off study protocol on a compassionate basis (having secondary progressive disease, an Expanded Disability Status Scale [EDSS] score of 6.0 or more, or a particularly disabling disease). The remaining 55 participants (37%) were treated on the study protocol and met the criteria. Criteria included relapsing-remitting MS, EDSS between 2.0 and 6.0, received treatment with at least one FDA-approved drug, and had at least two corticosteroid-treated relapses within the last year or one corticoid treated relapse and gadolinium enhancing lesions shown on an MRI.

A relatively low proportion of treatment-related complications (9%) occurred and no deaths were reported. There was significant improvement in the EDSS for the majority of patients, which was the primary objective of the study, and 80% of the participants achieved disease-free survival at two years after treatment.

Another study, HALT-MS, was a single arm, Phase 2 trial of immunoablation followed by autologous transplantation of stem cells. The study included 25 participants (with relapsing-remitting MS, EDSS score between 3.0 and 5.5 and two or more clinical relapses in 18 months despite other treatment). The primary objective was noted time until treatment failed. After two and three years of treatment, the overall event-free survival probability was 83% and 78%, respectively. The EDSS score improved a median of 0.5 after three years.

The third study was a single arm, Phase 2 of immunoablation followed by autologous transplantation of stem cells across three Canadian Hospitals (NCT01099930). The study included 24 participants with aggressive MS. All had multiple early relapses, an EDSS score of at least 3.0 with five years of diagnosis, and evidence of ongoing clinical disease activity despite at least one year of treatment.

All 23 surviving participants were free of clinical relapses and new gadolinium enhancing lesions for the duration of follow-up (median 6.7 years).

Seventeen participants (70%) had no more progression in EDSS scores after treatment and eight patients (35%) had sustained improvement in EDSS scores three years after treatment. The rate of brain atrophy was not substantially different from healthy volunteers.

The three studies offer several positive results for continued investment in the role of aHSCT for MS patients.

More recent studies in aHSCT indicate that the therapy might be more successful if done in the earlier inflammatory stages of MS. Ideal candidates may be patients less than 40 years old with a short disease duration of less than five years, recurring and disabling relapses, presence of inflammatory activity shown on brain MRI scans, and who were unresponsive to approved therapies.

However, a large, randomized clinical study comparing aHSCTs with the best approved therapies is still needed to confirm the role of stem cell transplant in MS management.

Note: Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.



Researchers Succeed at Generating Oligodendrocytes, Key to Myelin Renewal, in Tissue Created in Lab

Researchers at Case Western Reserve University School of Medicine have developed a cutting-edge laboratory technique able to turn human stem cells – special cells able to grow into any type of cell in the body – into brain-like tissues in a culture dish.

They intend to use their tool to study how myelination – the deposition of myelin around nerve cells – occurs in the central nervous system, and how diseases such as multiple sclerosis (MS) impair this process.

The experimental protocol to grow these structures outside an organis) is described in the study, “Induction of myelinating oligodendrocytes in human cortical spheroids,” published in the journal Nature Methods.

These structures, called “oligocortical spheroids,” are small spheres that contain all the major cell types usually found in the human brain, including oligodendrocytes — cells that produce myelin, which is the fatty substance that insulates nerve fibers. Previous cerebral organoid techniques failed to include oligodendrocytes.

“We have taken the organoid system and added the third major cell type in the central nervous system — oligodendrocytes — and now have a more accurate representation of cellular interactions that occur during human brain development,” Paul Tesar, PhD, associate professor of genetics and genome sciences at Case Western’s medical school and the study’s senior author, said in a press release.

Oligodendrocytes are essential to good brain health. Without these cells, myelin production is hampered and nerve cells cannot communicate effectively, and eventually they start to deteriorate. This is the starting point for many neurological disorders caused by myelin defects, including MS and rare pediatric genetic disorders like Gaucher disease.

Using this new organoid system and these myelin-producing cells, researchers intend to study the process of myelination — how it occurs in normal circumstances and how neurodegenerative diseases disrupt this process.

“This is a powerful platform to understand human development and neurological disease,” Tesar said. “Using stem cell technology we can generate nearly unlimited quantities of human brain-like tissue in the lab. Our method creates a ‘mini-cortex,’ containing neurons, astrocytes, and now oligodendrocytes producing myelin. This is a major step toward unlocking stages of human brain development that previously were inaccessible.”

Researchers not only demonstrated that they were capable of generating mature oligodendrocytes derived from human stem cells in vitro, but they also showed these cells were able to exert their function and produce myelin starting at week 20 in a culture dish.

Their improved organoid system could also be used to test the effectiveness of potential myelin-enhancing treatments.

“These organoids provide a way to predict the safety and efficacy of new myelin therapeutics on human brain-like tissue in the laboratory prior to clinical testing in humans,” said Mayur Madhavan, PhD, co-first author on the study.

To prove this point, researchers treated organoids with promyelinating compounds known to enhance myelin production in mice, and measured the rate and extent of oligodendrocyte generation and myelination.

Under normal conditions, adding promyelinating drugs to cultured organoids increased the rate and extent of oligodendrocyte generation and myelin production, the team reported.

But results differed in important ways using diseased organoids.  Specifically, treating organoids generated from patients with Pelizaeus-Merzbacher disease — a fatal genetic myelin disorder — brought an in vitro recapitulation of the patients’ symptoms.

“Pelizaeus-Merzbacher disease has been a complicated disorder to study due to the many different mutations that can cause it and the inaccessibility of patient brain tissue,” said Zachary Nevin, PhD, co-first author on the study. “But these new organoids allow us to directly study brain-like tissue from many patients simultaneously and test potential therapies.”

Altogether, these findings demonstrate that oligocortical spheroids could be a versatile in vitro system to study how myelination occurs in the central nervous system, and a possible model for testing new therapies for neurodegenerative disorders.

“Our method enables generation of human brain tissue in the laboratory from any patient,” Tesar said. “More broadly, it can accurately recapitulate how the human nervous system is built and identify what goes wrong in certain neurological conditions.”

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#AAN2018 – Stem Cell Transplant is Effective Treatment for ‘Aggressive’ MS, Study Shows

Autologous hematopoietic stem cell transplantation, also known as aHSCT, has been shown to be safe and highly effective to treat patients with “aggressive” multiple sclerosis. Tested in 19 patients, transplantation of stem cells was found to induce clinically meaningful improvements in disability.

These findings were shared at the 2018 Annual Meeting of the American Academy of Neurology (AAN) in Los Angeles, California.

aHSCT uses a patient’s own healthy bone marrow stem cells, in combination with a much less aggressive chemotherapy and/or radiation regimen, to prepare the patient for the transplant.

Previous studies have suggested that aHSCT is an effective strategy to treat patients with highly active relapsing-remitting MS (RRMS) who do not respond to available disease-modifying therapies (DMTs), and international guidelines advocate for its use in patients with “aggressive” MS.

To further demonstrate the potential of aHSCT as a treatment for “aggressive” MS, a research team evaluated its safety and effectiveness in MS patients who had not been treated previously with DMTs.

A total of 19 patients were treated across several clinical centers: seven patients were from Sheffield, U.K., seven from Uppsala, Sweden, four from Ottawa, Canada, and one patient was from Florence, Italy. All patients received aHSCT between May 2004 and May 2017.

In addition to aHSCT, patients were treated with BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy plus antithymocyte globulin (ATG) to reduce transplant rejection, or with Cytoxan (cyclophosphamide) with ATG, or the triple combination of Cytoxan, ATG, plus busulfan as conditioning regimens.

Patients had a median age of 33 years at diagnosis and received the aHSCT by a median time of nine years after symptom onset. They had a median disability score of 6.5 before the treatment, as determined by the Expanded Disability Status Scale (EDSS).

After a median follow-up period of 30 months, patients had a median EDSS score of 2.0, which represented a median improvement of 2 points (the higher the score, the worse the patient’s disability level).

None of the patients had clinical relapse following the transplant of stem cells.

Only three patients developed new brain lesions detectable by magnetic resonance imaging (MRI) at the first six-month follow-up evaluation, but no additional new lesions were detected in the following scans.

The adverse effects reported during the study were comparable to those previously observed in similar treatments. No deaths related to the treatment were reported.

Based on these preliminary results, the researchers concluded that aHSCT is “safe and highly effective in inducing rapid and sustain remission” in highly active MS, and “was associated with a significant improvement of [patient’s] level of disability.”

“aHSCT should be considered as first line therapy in patients with ‘aggressive’ MS,” the team concluded.

Another study presented at the AAN 2018 meeting further supports these findings, demonstrating the superior effectiveness of aHSCT over conventional DMTs for RRMS.

#AAN2018 – Blood Stem Cell Transplant Superior to DMDs in Highly Active RRMS, MIST Trial Shows

Autologous non-myeloablative hematopoietic stem cell transplant was found to be significantly better at reducing risks for disability in relapsing-remitting multiple sclerosis patients compared to disease-modifying drug therapies, interim results of the MIST clinical trial show.

The results will be shared at the 2018 Annual Meeting of the American Academy of Neurology.

Autologous non-myeloablative hematopoietic stem cell transplant previously was reported as a safe and effective therapy leading to long-term improvements in neurological disability in patients with RRMS.

This stem cell transplant strategy uses a patient’s own healthy bone marrow stem cells together with a much less aggressive combination of chemotherapy and/or radiation to prepare the patient for the transplant.

In the Phase 3 clinical trial MIST , a team of researchers evaluated how non-myeloablative HSCT compares to continuous DMD therapy.

They randomized a group of 110 RRMS patients being treated with DMDs, but who relapsed at least twice  in the year before randomization into two groups: one group received a chemotherapy drug (cyclophosphamide, sold under the brand name Cytoxan, among others) plus a suppressant of the immune system (to prevent HSCT rejection), followed by HSCT; the control group continued treatment with the most appropriate DMD prescribed by their neurologist.

Researchers analyzed the rate of treatment failure — defined as an increase of at least 1.0 point six sustained for at least 6 months, in the Expanded Disability Status Scale (EDSS).

“Patients on DMDs who failed after at least 1 year of treatment were allowed to crossover to HSCT,” researchers wrote.

A wide-selection of DMD therapies was included in the control group: interferons; Tysabri; Tecfidera ; Gilenya ; Copaxone, and Novantrone.

Other immune drugs in the control arm included corticosteroids, Cytoxan and Rituxan.

After a mean follow-up of three years, the results showed that treatment failure reached 60% of the population in the DMD control group , compared to 6% in the HSCT group.

Also, in the first year after HSCT, mean EDSS improved from 3.5 to 2.4, while it worsened from 3.3 to 3.9 in the control arm.

Overall, these findings support that HSCT’s effectiveness was a superior therapeutic compared to continued DMD treatment in RRMS patients with more than two relapses a year.

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Transforming Skin Cells Into Nerve Stem Cells Could Be a Way to Treat MS, Study Suggests

Reprogramming skin cells into brain stem cells, then transplanting them into the central nervous system may reduce inflammation and reverse the nerve cell damage in progressive multiple sclerosis, a mouse study shows.

Scientists have dubbed macrophages the immune system’s big eaters because they engulf abnormal cells like cancer in addition to invaders like viruses and bacteria.

Special classes of macrophages live in a number of organs, including the brain and spinal cord, where they’re called microglia.

Although they protect the body, microglia can participate in the development of progressive forms of MS by attacking the central nervous system, causing nerve cell damage. MS is an autoimmune disease, or one in which the immune system can attack healthy tissue besides invaders.

Recent studies have suggested that neural stem cells, which have the capacity to differentiate into any type of nerve cell, can regulate immune response and inflammation in the central nervous system.

At one point, researchers obtained neural stem cells from embryos. But this technique generated only a fraction of the cells needed for treatments.

Meanwhile, doctors have tried to avoid collecting stem cells from someone with a different genetic profile than the patient because this increases the risk that the immune system will attack them once they’re transplanted.

University of Cambridge scientists decided to try reprogramming skin cells into neural stem cells. The idea behind the mouse study was that using skin cells from the same person who will receive the stem cells will reduce the chance that the immune system will attack the stem cells.

In the mouse study, the team discovered a link between higher than normal levels of a small metabolite, called succinate, and chronic MS. The metabolite prompts macrophages and microglia to generate inflammation in the cerebrospinal fluid that bathes the brain and spinal cord.

Transplanting neural stem cells and progenitors of these stem cells into the cerebrospinal fluid of mice improved the animals’ chronic nerve cell inflammation. The stem cells reduced the animals’ succinate levels and switched their macrophages and microglia from a pro- to an anti-inflammatory state. This led to a decrease in inflammation and less damage to the central nervous system.

“Our mouse study suggests that using a patient’s reprogrammed cells could provide a route to personalized treatment of chronic inflammatory diseases, including progressive forms of MS,” Stefano Pluchino, a principal researcher in Cambridge’s Department of Clinical Neurosciences, said in a press release.

“This is particularly promising as these cells should be more readily obtainable than conventional neural stem cells and would not carry the risk of an adverse immune response,” said Pluchino, the study’s lead author.

Luca Peruzzotti-Jametti, a Wellcome Trust research training fellow, said the discovery would not have been possible without a multidisciplinary collaboration. “We made this discovery by bringing together researchers from diverse fields, including regenerative medicine, cancer, mitochondrial biology, inflammation and stroke, and cellular reprogramming.”

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