New approach to Multiple Sclerosis treatment using immunosuppression and stem cells shows promise

New clinical trial results provide evidence that high-dose immunosuppressive therapy followed by transplantation of a person’s own blood-forming stem cells can induce sustained remission of relapsing-remitting multiple sclerosis (MS).

Five years after receiving the treatment, called high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), 69 percent of trial participants had survived without experiencing progression of disability, relapse of MS symptoms or new brain lesions. Notably, participants did not take any MS medications after receiving high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT). Other studies have indicated that currently available MS drugs have lower success rates.

The trial, called HALT-MS, was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted by the NIAID-funded Immune Tolerance Network (ITN). The researchers published three-year results from the study in December 2014, and the final five-year results appear in Neurology, the medical journal of the American Academy of Neurology.

“These extended findings suggest that one-time treatment with high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) may be substantially more effective than long-term treatment with the best available medications for people with a certain type of MS,” said NIAID Director Anthony S. Fauci, M.D. “These encouraging results support the development of a large, randomized trial to directly compare high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) to the standard of care for this often-debilitating disease.”

In HALT-MS, researchers tested the safety, efficacy and durability of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) in 24 volunteers aged 26 to 52 years with relapsing-remitting multiple sclerosis (MS) who, despite taking clinically available medications, experienced active inflammation, evidenced by frequent severe relapses, and worsened neurological disability.

The experimental treatment aims to suppress active disease and prevent further disability by removing disease-causing cells and resetting the immune system. During the procedure, doctors collect a participant’s blood-forming stem cells, give the participant high-dose chemotherapy to deplete the immune system, and return the participant’s own stem cells to rebuild the immune system. The treatment carries some risks, and many participants experienced the expected side effects of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), such as infections. Three participants died during the study; none of the deaths were related to the study treatment.

Five years after high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT), most trial participants remained in remission, and their MS had stabilized. In addition, some participants showed improvements, such as recovery of mobility or other physical capabilities.

“Although further evaluation of the benefits and risks of high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) is needed, these five-year results suggest the promise of this treatment for inducing long-term, sustained remissions of poor-prognosis relapsing-remitting MS,” said Richard Nash, M.D., of Colorado Blood Cancer Institute and Presbyterian-St. Luke’s Hospital. Dr. Nash served as principal investigator of the HALT-MS study.

If these findings are confirmed in larger studies, high-dose immunosuppressive therapy and autologous hematopoietic cell transplant (HDIT/HCT) may become a potential therapeutic option for patients with active relapsing-remitting multiple sclerosis (MS), particularly those who do not respond to existing therapies,” said Daniel Rotrosen, M.D., director of NIAID’s Division of Allergy, Immunology and Transplantation.

Citation: Nash, Richard A., George J. Hutton, Michael K. Racke, Uday Popat, Steven M. Devine, Linda M. Griffith, Paolo A. Muraro et al. “High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report.” JAMA neurology 72, no. 2 (2015): 159-169.
DOI: 10.1212/WNL.0000000000003660
Research funding: NIH/National Institute of Allergy and Infectious Diseases.
Adapted from press release by NIH/National Institute of Allergy and Infectious Diseases.

Multiple Sclerosis medication alemtuzumab can trigger severe B cell mediated brain inflammation

The multiple sclerosis (MS) therapy alemtuzumab can trigger severe, unpredictable side effects. This was the finding by a team led by Prof Dr Aiden Haghikia and Prof Dr Ralf Gold from the Department of Neurology of the Ruhr-Universität Bochum at St. Josef’s Hospital. In the journal Lancet Neurology, the scientists report on two patients for whom the infusion of alemtuzumab significantly worsened symptoms. The team also describes a treatment that successfully curbed the harmful side effects.

Alemtuzumab is a therapeutic antibody that docks to the protein CD52 on the surface of certain immunocytes, mainly T and B lymphocytes, leading to the depletion of almost all lymphocytes. It was already known from the approval studies that a quarter of the treated patients display mostly minor side effects, called secondary autoimmune processes: immunocytes turn against cells produced naturally in the body, predominantly in the thyroid gland; but the kidneys and platelets can also be affected.

The two patients described in the Lancet Neurology study received alemtuzumab because they had highly active MS, i.e. despite numerous previous treatments, they suffered from severe illness relapses with inflammation in the central nervous system. Six months after the treatment, these symptoms had worsened significantly. Using MRI, the researchers discovered a kind of new inflammation mode: they found vast areas in the brain with numerous ring enhancing lesion. The patients had not displayed this pattern in their previous medical history.

It is currently unclear whether the observed adverse events represent increased MS activity or an independent secondary autoimmune process.

In both cases, the neurologists were able to curb the side effects, and the observed ring-shaped deposits in the brain receded. Even a year after the treatment, the patients were still in a stable condition. Besides a blood plasma exchange, they treated both with the antibody rituximab that is directed against B lymphocytes. The researchers suspect that precisely these immunocytes were responsible for the observed side effect.

The authors propose that the measures they applied could also benefit other patients who develop similar adverse events under alemtuzumab.

Citation: Haghikia, Aiden, Calliope A. Dendrou, Ruth Schneider, Thomas Grüter, Thomas Postert, Mike Matzke, Heike Stephanik, Lars Fugger, and Ralf Gold. “Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy.” The Lancet Neurology 16, no. 2 (2017): 104-106.
DOI: 10.1016/S1474-4422(16)30382-9

Adapted from press release by Ruhr-Universitaet-Bochum.

Multiple sclerosis pathogenesis: association between amount of leaked hemoglobin and severity of brain shrinkage

A leak of a protein called hemoglobin from damaged red blood cells may be associated with brain shrinkage in multiple sclerosis. This is the conclusion of a team from Imperial College London, whose early-stage findings suggest treatments that lower levels of hemoglobin could slow progression of the disease. Haemoglobin carries iron and oxygen around the body in red blood cells.

The research, which involved 140 patients with an advanced form of the disease, called secondary progressive multiple sclerosis, has just passed peer review on a new publishing platform, Wellcome Open Research.

Professor Charles Bangham, the lead author of the study from the Department of Medicine at Imperial, said: “These are exciting but early results. If further studies confirm them, they may suggest new avenues of treatment and hopefully more options to offer patients in the future.”

Multiple sclerosis (MS) affects around 100,000 people in the UK. The lifelong condition affects the brain and spinal cord, and results in nerves being destroyed. The symptoms and the severity of the illness vary widely from person to person but often include fatigue, vision problems, muscle spasms and impaired mobility. At first, patients tend to experience repeated episodes of the condition, but symptoms improve between each period of illness. However around 65 percent of patients eventually develop a more severe form of the disease, called secondary progressive multiple sclerosis. In this phase, which generally starts around 15 years after the initial MS diagnosis, the symptoms become steadily worse, with no periods of improvement.

The condition also causes brain cells to die, and on average the brain shrinks by about 0.3 per cent a year in secondary progressive MS. Previous research has found high amounts of iron deposited around blood vessels in the brain. Although the mineral is crucial for our bodies to function, it is toxic at high levels – and scientists have suggested this may trigger the death of brain cells in MS. In the new study, the team suggests that hemoglobin, which carries iron and oxygen around the body may cause these high iron levels.

Haemoglobin is usually contained within the red blood cells. However, previous research suggests red blood cells in MS patients are, for unknown reasons, more fragile than normal and break apart easily.

When red blood cells break down they release hemoglobin into the bloodstream. Normally, the protein would then be prevented from entering the brain by a ‘checkpoint’ between the bloodstream and the brain. However, in MS patients this checkpoint – called the blood-brain barrier – is weakened, allowing hemoglobin to sail through.

The team suggests that once hemoglobin enters the brain it is broken down by an enzyme called haem oxygenase I, which has been found at high levels in the brains of MS patients. The destruction of hemoglobin causes iron to be released into the brain.

Professor Bangham explained: “The iron escapes from the hemoglobin, and may then result in the cell damage and brain shrinkage we see in secondary progressive MS.”

The researchers stress that there are no dietary methods for reducing hemoglobin levels, and people should not remove iron from their diet. “Iron eaten in foods has no effect on the levels of iron that accumulate in the brain. It is the hemoglobin levels, rather than iron that needs to be tackled. Iron is vital for the body, and should not be reduced in the diet,” said Professor Bangham.

In the study, the team found that the MS patients had high levels of a compound called serum lactate dehydrogenase, which is released when red blood cells disintegrate. In the research, the scientists analyzed blood samples of 140 patients with secondary progressive MS, taken over a two-year period, and looked for any proteins raised above normal levels. The team also analyzed brain scans of the patients, as well as blood samples from 20 healthy controls, and 40 patients with other medical conditions apart from MS. They found that blood levels of “free” hemoglobin – hemoglobin that has escaped from the red blood cells – were significantly higher in MS patients with the greatest amount of brain shrinkage. The researchers calculated that a 30 percent increase in free hemoglobin levels resulted in an increased rate of brain shrinkage by 0.1 per cent. This could make a significant difference to a patient’s symptoms.

Professor Bangham explained that the findings were unexpected: “We were amazed by the results, and we were surprised by the size of the apparent effect of hemoglobin on brain shrinkage. Over a number of years, it could significantly impact a patient’s symptoms.” He added that high hemoglobin levels are not the only factor leading to brain shrinkage, but could be a significant contributor.

Existing trials are testing potential MS treatments that mop up excess iron. Professor Bangham questions whether this is the best approach. “It may be more effective to look at ways of removing excess hemoglobin from the blood, rather than iron. There are a number of drugs that do this, although none have been used for multiple sclerosis.”

Furthermore, testing hemoglobin in the blood would not be helpful. This would only show that brain shrinkage is occurring – which would already be detectable on a scan.

The study was performed on patients who had been taking part in a clinical trial, examining the effect of statins on secondary progressive MS. The trial showed statins may have a beneficial effect on brain shrinkage, although this doesn’t seem to be linked to hemoglobin levels said Professor Bangham. “We are still unsure how the statins work, but it seems to be completely separate from the way hemoglobin triggers brain shrinkage.”

The team is now working on further studies to confirm the findings and explore what treatments may tackle high levels of hemoglobin in the blood.

Citation: Alex Lewin, Shea Hamilton, Aviva Witkover, Paul Langford, Richard Nicholas, Jeremy Chataway, Charles R.M. Bangham.  “Free serum hemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis”. Wellcome Open Research 2016 vol: 1 pp: 10.
DOI: 10.12688/wellcomeopenres.9967.1
Research funding: Wellcome trust, Medical Research Council
Adapted from press release by Imperial College London.

Treating traumatic nerve injury with 4-aminopyridine

Researchers at the University of Rochester Medical Center believe they have identified a new means of enhancing the body’s ability to repair its own cells, which they hope will lead to better diagnosis and treatment of traumatic nerve injuries, like those sustained in car accidents, sports injuries, or in combat. The research team showed that a drug previously approved for chronic nerve disease, multiple sclerosis can ‘wake up’ damaged peripheral nerves and speed repair and functional recovery after injury.

Structure of 4-amionpyridine (4AP) molecule
credit: Wikipedia user Yikrazuul
The study appearing in EMBO Molecular Medicine demonstrates for the first time that 4-aminopyridine (4AP), a drug currently used to treat patients with the chronic nerve disease, multiple sclerosis, has the unexpected property of promoting recovery from acute nerve damage. Although this drug has been studied for over 30 years for its ability to treat chronic diseases, this is the first demonstration of 4-aminopyridine’s benefit in treating acute nerve injury and the first time those benefits were shown to persist after treatment was stopped.
Study authors, John Elfar, M.D., associate professor of Orthopaedics, and Mark Noble, Ph.D., Martha M. Freeman, M.D., Professor of Biomedical Genetics, and their laboratory team, found that daily treatment with 4-aminopyridine promotes repair of myelin, the insulating material that normally surrounds nerve fibers. When this insulation is damaged, as occurs in traumatic peripheral nerve injury, nerve cell function is impaired. These researchers found that 4-aminopyridine treatment accelerates repair of myelin damage and improvement in nerve function.

These findings advance an area of research that has been stagnant for nearly 30 years and may address unmet needs of traumatically injured patients in the future. The current standard of care for traumatic peripheral nerve injury is “watchful waiting” to determine whether a nerve has the ability to spontaneously recover, or if it will require surgery.

The problem, says Elfar, a Sports Medicine surgeon specializing in hand, wrist, elbow and shoulder repairs, is that “the patient who may recover is recovering so slowly that nerve-dependent tissues are in jeopardy, and the patient who needs surgery has to wait for weeks for the diagnosis that surgery is appropriate. That delay means that surgery is less effective.”

Elfar’s and Noble’s team, which includes Kuang-Ching Tseng, Ph.D., former graduate student in the Center for Musculoskeletal Research at the University of Rochester Medical Center and first author of the study, also found that treating mice with a single dose of 4-aminopyridine one day after nerve crush injury improved muscle function within an hour. In this model, nerves are damaged, but not completely severed. The team believes this finding may suggest that 4-aminopyridine could be used immediately after an injury to diagnose whether a nerve is severed, however, further studies are required to determine if this will work in humans.

If their results can be translated into humans, it could mean earlier and more rapid diagnosis of traumatic peripheral nerve injuries, enabling earlier surgery and better outcomes for patients whose nerves have been completely severed. For patients whose nerves are still connected, 4-aminopyridine (4AP) treatment could offer a new means to speed recovery, where none has previously existed.

The Department of Defense has recognized the potential impact this could have for soldiers in combat situations and granted $1 million to Elfar and Noble to continue this research over the next three years.

“This is an ideal outcome for development of a treatment to promote tissue regeneration,” said Noble. “The drug we use to identify injuries that need repair of their insulating myelin is the same drug we use to promote the needed repair. As 4-aminopyridine (4AP) has been well-studied in chronic injuries, and is approved for treating multiple sclerosis, the new benefits we discovered can be explored rapidly and much more cheaply than is needed for developing an entirely new drug.”

Beyond nerve injuries sustained during accidents or in the line of duty, the researchers are also looking into using 4-aminopyridine to repair nerve conduction after routine surgeries. Removal of the prostate, for example, can cause nerve damage that leaves patients with incontinence and erectile dysfunction, the burden and stigma of which may contribute to prostate cancer patients refusing the surgery.

Elfar and Noble hope to begin a clinical trial to test this in the near future. The proposed trial has been approved by the Food and Drug Administration (FDA), and University of Rochester researchers and clinicians are completing the planning stages before recruiting participants.

Citation: Tseng, Kuang‐Ching, Haiyan Li, Andrew Clark, Leigh Sundem, Michael Zuscik, Mark Noble, and John Elfar. “4‐Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.” EMBO Molecular Medicine (2016): e201506035.
DOI: 10.15252/emmm.201506035
Research funding: National Institutes of Health, New York State Spinal Cord Injury Research Program, American Foundation for Surgery of the Hand, Friends of Nancy Lieberman Fund.
Adapted from press release by University of Rochester Medical Center.