Archive for December, 2012
Researchers have identified a protein that may be a target of the immune attack in some people with multiple sclerosis, according to a new study published in The New England Journal of Medicine. An immune response to this protein – a protein called “KIR4.1,” which is found on several types of brain cells – was observed in the serum of 47% of people with multiple sclerosis who were tested. Further research is needed to confirm these findings, and to understand what the role of this protein may play in multiple sclerosis and its potential for developing new treatments. Rajneesh Srivastava MSc and Bernhard Hemmer MD (Technische Universität, Munich) led the international team, who are supported by grants from the German Ministry for Education and Research and the National MS Society, among others.
The spinal fluid of most people with multiple sclerosis contains increased amounts of the antibody IgG. IgG antibodies are present almost exclusively in infectious and inflammatory disorders and are usually directed against the disease-causing agent. However, previous attempts to identify antigens to which antibodies are targeted in multiple sclerosis have failed. The current study focused on the serum portion of blood samples from people with multiple sclerosis and from others, rather than on spinal fluid.
In a series of experiments, the authors screened serum samples from people with multiple sclerosis and observed that IgG antibodies were attaching themselves to specific myelin-making cells. Using “proteomics” – advanced technology that scans hundreds of thousands of proteins simultaneously – they screened numerous proteins on the cells. They identified the protein KIR4.1 as the target of the IgG reaction. KIR4.1 is an ion channel; these are proteins that are active on the surfaces of several types of brain cells and are critical for cell function.
The team then developed a method of testing people for the presence of antibodies against KIR4.1 in serum samples, and found antibodies to KIR4.1 in a substantial proportion of people with multiple sclerosis in comparison with others tested. In fact, the antibodies were found in serum of 186 of 397 (46.9%) people with multiple sclerosis, versus only 3 out of 329 people with other neurologic disorders, and in none out of 59 people without disease.
Further studies revealed that when anti-KIR4.1 antibodies that were obtained from people with multiple sclerosis were injected into mice, abnormalities in the nervous system occurred. In previous studies, KIR4.1 has been shown to be important in myelin formation, so the authors conclude that this protein is a plausible candidate to be a target of the immune attack in at least some people who have multiple sclerosis. The investigators did not observe any clinical or other differences in people with multiple sclerosis who had the antibodies versus those who did not. How this protein may be involved in multiple sclerosis, and whether this finding will lead to new approaches to treating MS, awaits further research.
In an accompanying editorial, Anne H Cross MD (Washington University School of Medicine, St. Louis) and Emmanuelle Waubant MD PhD (University of California, San Francisco) discuss the strengths of this study. “First, the authors used an unbiased approach to search for serum antibodies specific to patients with multiple sclerosis and, once they found them, methodically sought the target,” they write.
The specific role of the protein awaits definition, especially since half of the people with multiple sclerosis did not have the antibodies to KIR4.1. They note that even if these antibodies arise sometime after the nervous system has already sustained damage in multiple sclerosis, “it is conceivable that they may perpetuate destruction of the central nervous system.”
Source: News Release
National Multiple Sclerosis Society
July 11, 2012
Wayne State University School of Medicine researchers, working with colleagues in Canada, have found that 1 or more substances produced by a type of immune cell in people with multiple sclerosis (MS) may play a role in the disease’s progression. The finding could lead to new targeted therapies for multiple sclerosis treatment.
B cells, said Robert Lisak MD, professor of neurology at Wayne State and lead author of the study, are a subset of lymphocytes (a type of circulating white blood cell) that mature to become plasma cells and produce immunoglobulin, proteins that serve as antibodies. The B cells appear to have other functions, including helping to regulate other lymphocytes, particularly T cells, and helping maintain normal immune function when healthy.
In patients with multiple sclerosis, the B cells appear to attack the brain and spinal cord, possibly because there are substances produced in the nervous system and the meninges—the covering of the brain and spinal cord—that attract them. Once within the meninges or central nervous system, Lisak said, the activated B cells secrete 1 or more substances that do not seem to be immunoglobulins but that damage oligodendrocytes, the cells that produce a protective substance called myelin.
The B cells appear to be more active in patients with multiple sclerosis, which may explain why they produce these toxic substances and, in part, why they are attracted to the meninges and the nervous system.
The brain, for the most part, can be divided into gray and white areas. Neurons are located in the gray area, and the white parts are where neurons send their axons—similar to electrical cables carrying messages—to communicate with other neurons and bring messages from the brain to the muscles. The white parts of the brain are white because oligodendrocytes make myelin, a cholesterol-rich membrane that coats the axons. The myelin’s function is to insulate the axons, akin to the plastic coating on an electrical cable. In addition, the myelin speeds communication along axons and makes that communication more reliable. When the myelin coating is attacked and degraded, impulses—messages from the brain to other parts of the body—can "leak" and be derailed from their target. Oligodendrocytes also seem to engage in other activities important to nerve cells and their axons.
The researchers took B cells from the blood of 7 patients with relapsing-remitting multiple sclerosis and from four healthy patients. They grew the cells in a medium, and after removing the cells from the culture collected material produced by the cells. After adding the material produced by the B cells, including the cells that produce myelin, to the brain cells of animal models, the scientists found significantly more oligodendrocytes from the multiple sclerosis group died when compared to material produced by the B cells from the healthy control group. The team also found differences in other brain cells that interact with oligodendrocytes in the brain.
"We think this is a very significant finding, particularly for the damage to the cerebral cortex seen in patients with MS, because those areas seem to be damaged by material spreading into the brain from the meninges, which are rich in B cells adjacent to the areas of brain damage," Lisak said.
The team is now applying for grants from several sources to conduct further studies to identify the toxic factor or factors produced by B cells responsible for killing oligodendrocytes. Identification of the substance could lead to new therapeutic methods that could switch off the oligodendrocyte-killing capabilities of B cells, which, in turn, would help protect myelin from attacks.
The study, "Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro," was published in the May 2012 edition of the Journal of Neuroimmunology and was recently featured in a National Multiple Sclerosis Society bulletin.
The research was supported by a National Multiple Sclerosis Society Collaborative MS Research Center Award, the Canadian Institutes of Health Research, and the Multiple Sclerosis Society of Canada.
Source: News Release
Wayne State University – Office of the Vice President for Research
July 31, 2012
Researchers at the National Institutes of Health have found evidence that a unique type of immune cell contributes to multiple sclerosis (MS). Their discovery helps define the effects of one of the newest drugs under investigation for treating multiple sclerosis – daclizumab – and could lead to a new class of drugs for treating multiple sclerosis and other autoimmune disorders.
In these disorders, the immune system turns against the body’s own tissues. Ongoing clinical trials have shown that daclizumab appears to help quiet the autoimmune response in multiple sclerosis patients, but its precise effects on the legions of cells that make up the immune system are not fully understood.
The new study, published in Science Translational Medicine, shows that one effect of daclizumab is to thin the ranks of lymphoid tissue inducer (LTi) cells. These cells are known to promote the development of lymph nodes and related tissues during fetal life, but their role during adulthood has been unclear. The new study marks the first time that LTi cells have been implicated in any human autoimmune disorder.
"While further study is required to confirm the role of LTi cells in autoimmunity, our results point to the cells as a promising target for the development of new drugs to treat autoimmune disorders," said Bibiana Bielekova MD, an investigator at NIH’s National Institute of Neurological Disorders and Stroke (NINDS).
Dr Bielekova and her team found that among multiple sclerosis patients participating in clinical trials of daclizumab, the number of LTi cells was elevated in patients not receiving daclizumab compared to those on the drug. Patients receiving daclizumab also had reduced signs of inflammation in the cerebrospinal fluid that surrounds the brain. And the researchers found that daclizumab appears to steer the body away from producing LTi cells, in favor of another cell type that counteracts autoimmunity.
The newer, sophisticated drugs for relapsing-remitting multiple sclerosis target key cells and molecules responsible for triggering and maintaining autoimmunity. Cytotoxic T cells are known to lead the attack. Antibodies appear to help reinforce it.
Daclizumab is a lab-engineered antibody, or monoclonal antibody, that alters signaling by interleukin-2 (IL-2), a key factor that mobilizes T cells. In a large clinical trial (NCT00109161), it has shown promise as an add-on therapy for patients taking the approved multiple sclerosis drug interferon-beta. Another ongoing trial (NCT00390221) is investigating whether or not daclizumab is effective as a stand-alone therapy for reducing relapses in multiple sclerosis.
The drug was designed to suppress T cell responses to IL-2, and it does so – but Dr Bielekova had found previously that this suppression is indirect and depends on other immune cells. For example, 1 effect of daclizumab is to stimulate the nonspecialized counterparts of T cells, called natural killer cells. These cells in turn suppress T cell activity.
In their new study, Dr Bielekova and her team discovered that daclizumab’s stimulatory effect on natural killer cells is paired with an inhibitory effect on LTi cells. They found evidence that the drug, via its effects on IL-2 signaling, acts on a type of stem cell. The drug appears to decrease the likelihood that this stem cell will develop into LTi cells, and sway it toward becoming natural killer cells.
"This helps explain why natural killer cells are activated and their numbers are expanded by daclizumab therapy," Dr Bielekova said. Meanwhile, she said, the drop in LTi cells was "intriguing" in itself, given the cells’ role in lymph node development.
Lymph nodes are patches of tissue where T cells and antibody-producing B cells set up camp. Inside the nodes, T cells and B cells are found in clusters called lymphoid follicles, where they wait for a signal that the body is under siege from infection. In autoimmune disorders, abnormal lymphoid follicles can develop and contribute to the autoimmune response. Secondary progressive multiple sclerosis, in particular, is associated with abnormal lymphoid follicles in the connective tissues (or meninges) surrounding the brain. These are believed to contribute to chronic brain inflammation in multiple sclerosis, eventually leading to shrinkage of the brain.
Dr Bielekova and her team reasoned that daclizumab, by suppressing LTi cells, should reduce the growth of lymphoid follicles. Because it is not possible to visualize these follicles in the live brain, the researchers measured the effects of daclizumab on markers of inflammation in the cerebrospinal fluid. They found that CXCL13, a protein linked to lymphoid growth, and the IgG index, a measure of antibody production, decreased by an average of 50.4% and 13.5%, respectively, in trial participants who took the drug for 6.5 months.
"To our knowledge, no other MS therapy reduces IgG index," Dr Bielekova said.
She cautioned that these data provide only an indirect link between LTi cells and brain inflammation in multiple sclerosis. If further research confirms that the cells play an important role in multiple sclerosis or other autoimmune disorders, "pursuing the development of new drugs to selectively inhibit LTi cells could be a useful therapeutic strategy," she said.
This study was funded by the NIH-NINDS intramural research program. The lead authors were Justin Perry and Sungpil Han. Mr. Perry was a fellow in NIH’s Postbaccalaureate Intramural Research Training Award program, and is currently a PhD student in the neuroscience program at Washington University in St Louis. Mr Han is an MD-PhD student at Pusan National University in South Korea, and is supported in part by a fellowship from the Korea Research Foundation to study at NIH. Patient data were derived from a small completed trial (NCT00071838) that showed that daclizumab may reduce lesions in relapsing-remitting multiple sclerosis, and from an ongoing trial to investigate the drug’s mode of action (NCT01143441).
Source: News Release
National Institute of Neurological Disorders and Stroke
August 1, 2012
New MRI research shows that changes in brain blood flow associated with vein abnormalities are not specific for multiple sclerosis and do not contribute to its severity, despite what some researchers have speculated. Results of the research are published online in the journal Radiology.
"MRI allowed an accurate evaluation of cerebral blood flow that was crucial for our results," said Simone Marziali MD, from the Department of Diagnostic Imaging at the University of Rome Tor Vergata in Rome.
Recent reports suggest a highly significant association between multiple sclerosis and chronic cerebrospinal venous insufficiency (CCSVI), a condition characterized by compromised blood flow in the veins that drain blood from the brain. This strong correlation has generated substantial attention from the scientific community and the media in recent years, raising the possibility that multiple sclerosis can be treated with endovascular procedures like stent placement. However, the role of brain blood flow alterations on multiple sclerosis patients is still unclear.
To investigate this further, Italian researchers compared brain blood flow in 39 multiple sclerosis patients and 26 healthy control participants. Twenty-five of the multiple sclerosis patients and 14 of the healthy controls were positive for CCSVI, based on Color-Doppler-Ultrasound (CDU) findings. The researchers used dynamic susceptibility contrast-enhanced (DSC) MRI to assess blood flow in the brains of the study groups. DSC MR imaging offers more accurate assessment of brain blood flow than that of CDU. MRI and CDU were used to assess 2 different anatomical structures.
While CCSVI-positive patients showed decreased cerebral blood flow and volume compared with their CCSVI-negative counterparts, there was no significant interaction between multiple sclerosis and CCSVI for any of the blood flow parameters. Furthermore, the researchers did not find any correlation between the cerebral blood flow and volume in the brain’s white matter and the severity of disability in multiple sclerosis patients.
The results suggest that CCSVI is not a pathological condition correlated with multiple sclerosis, according to Dr Marziali, but probably just an epiphenomenon—an accessory process occurring in the course of a disease that is not necessarily related to the disease. This determination is important because, to date, studies of the prevalence of CCSVI in multiple sclerosis patients have provided inconclusive results.
"This study clearly demonstrates the important role of MRI in defining and understanding the causes of MS," Dr Marziali said. "I believe that, in the future, it will be necessary to use powerful and advanced diagnostic tools to obtain a better understanding of this and other diseases still under study."
Source: News Release
Radiological Society of North America
August 20, 2012
A research study conducted by Dr Jesus Lovera, Assistant Professor of Neurology at LSU Health Sciences Center New Orleans, and colleagues has found that the herbal supplement ginkgo biloba does not improve cognitive function in patients with multiple sclerosis (MS.) Cognitive impairment affects 40% to 60% of people with multiple sclerosis, most commonly affecting their processing speed, memory, and executive skills. The research findings were published online ahead of print in Neurology on September 5, 2012.
This study followed up on a promising earlier small study by Dr Lovera and his colleagues that had shown improvement in cognitive function with ginkgo biloba in people with multiple sclerosis. Some studies have also shown improvement after treatment with Ginkgo biloba in people with Alzheimer disease.
"Ginkgo biloba supplements are frequently used by people with multiple sclerosis. Ginkgo appeared beneficial in a prior small pilot study we had done," said Dr Jesus Lovera, a neurologist at LSU Health Sciences Center New Orleans who specializes in multiple sclerosis.
The researchers wanted to conduct a larger more robust study to determine the validity of the preliminary results. One hundred twenty people with multiple sclerosis were randomized to either the group treated with 120 mg of ginkgo biloba twice a day, or to the group taking matching placebo tablets. Participants were treated for 12 weeks and then underwent a battery of cognitive tests. Participants and their families also answered standardized questionnaires about their cognitive function and social integration. The tests found that there were no statistically significant improvements in cognitive function between the 2 groups.
"Unfortunately we did not see any improvement with ginkgo in this new study," notes Dr Lovera. "Several drugs such as Namenda and Aricept that work for people with Alzheimer’s have been tested without success in people with MS. Unfortunately now Ginkgo is added to the list of therapies thought to be effective in Alzheimer’s disease that failed to improve cognitive performance in MS."
Although the study provides solid evidence, the researchers noted several limitations. Participants were treated for only 12 weeks and perhaps that was not long enough to modify the disease. The median duration of multiple sclerosis was 20 years, and it is possible that Ginkgo may improve cognitive function earlier in the multiple sclerosis disease process. It is also possible that there could have been a positive effect in participants with more severe impairments than those in this study. Additional functional assessments that measure performance in real-life situations may also have detected an effect that was missed by limiting the outcome measures to cognitive tests and questionnaires.
The team also included researchers from the Portland VA Medical Center, Puget Sound Health Care System, University of Washington, and Oregon Health & Science University. The US Department of Veterans Affairs supported the research.
Source: News Release
Louisiana State University Health Sciences Center
September 12, 2012
An extract from the plant Cannabis sativa (trade name Sativex®) was approved in May 2011 for patients suffering from moderate to severe spastic paralysis and muscle spasms due to multiple sclerosis. In an early benefit assessment pursuant to the "Act on the Reform of the Market for Medicinal Products” (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether the new drug, which is used as a mouth spray, offers an added benefit over the optimized standard therapy. However, no such added benefit can be inferred from the dossier, as the drug manufacturer deviated from the specifications of the Federal Joint Committee (G-BA) and chose a different comparator therapy.
The extract from Cannabis sativa, which contains the active ingredient combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), is approved as add-on therapy to the already used antispastic drugs. Usually, drugs such as baclofen or tizanidine are given to treat muscle spasms. The cannabis extract can be considered when, despite an individual, patient-tailored use of these drugs, the symptoms caused by spasticity cannot be adequately relieved.
The G-BA specified an optimized standard therapy containing baclofen, tizanidine, or drugs that are approved for the treatment of spasticity in underlying neurologic diseases as the appropriate comparator therapy. At least 2 previous attempts at treatment were to have been made, in each of which different oral antispastic (spasmolytic) drugs had been used in an optimum way. Again, at least 1 product was to have contained the active ingredients baclofen or tizanidine. The aim of the assessment by IQWiG was to compare the additional administration of the Cannabis sativa extract with other available possibilities for optimizing treatment and to assess the added benefit.
However the manufacturer deviated from this specification of the G-BA, without providing adequate justification for doing so. In its dossier, the manufacturer drew no conclusions about the extent and probability of the added benefit compared to the appropriate comparator therapy specified by the G-BA. The studies submitted by the manufacturer were not suitable for reaching conclusions on added benefit in comparison with an optimized standard therapy. This was because in none of these studies was it planned to optimize the antispastic premedication. Instead, this treatment was to be continued unchanged. Therefore there is no proof from the manufacturer’s dossier of an added benefit of Cannabis sativa extract compared to the appropriate comparator therapy of the G-BA.
The dossier assessment is part of the overall procedure for early benefit assessment conducted by the G-BA. After publication of the manufacturer’s dossier and its assessment by IQWiG, the G-BA initiates a formal commenting procedure which provides further information and can result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment.
The following extract (PDF, 86 kB) provides an overview of the results of the benefit assessment by IQWiG.
Source: News Release
Institute for Quality and Efficiency in Health Care
September 17, 2012
Scientists may be one step closer to predicting the uncertain course of relapsing-remitting multiple sclerosis (MS), a disease that can lay dormant for months or years, thanks to the discovery of a unique genetic marker. The marker, detailed by researchers in the August edition of The Journal of Immunology, is the first of its kind to be directly linked to multiple sclerosis.
The study, supported by funding from both the National Institutes of Health (NIH) and the Ohio State Center for Clinical and Translational Science (CCTS) was conducted by a team of scientists with The Ohio State University using blood samples from patients with multiple sclerosis, as well as mouse models. Researchers uncovered the molecule miR-29, while working to identify a biomarker in the blood that could indicate if a patient had an ongoing inflammatory response, such as multiple sclerosis.
“Our research was inspired by the knowledge gap that existed between microRNA and MS, as well as the unpredictable nature of MS,” said Kristen Smith PhD, principal investigator, who received a “mentorship grant” to conduct the study alongside senior scientists at The Ohio State University Wexner Medical Center. “By identifying a unique marker associated with MS, we hope to inspire a relatively noninvasive test that could identify and predict the course of the disease, helping clinicians tailor therapies to disease progression.”
miR-29 is a member of a group of microRNAs (miRNAs), which are known as critical regulators of the immune system. miRNAs are a relatively new discovery, with nearly 1400 having been identified to date. In addition to regulating the immune system, miRNAs also regulate gene expression. Previous research has shown miR-29 is responsible for regulating Th1 cells, a type of white blood cell that provides protective immune responses against infection. Uncontrolled, these cells can produce excessive inflammation, leading to tissue damage and autoimmune diseases, such as multiple sclerosis.
Despite the known relationship between miRNAs and the immune response, research regarding the connection between miRNAs found in Th1 cells and autoimmune disorders driven by these uncontrolled white blood cells had not been conducted until now.
“Since we knew miRNAs play an important role in creating and controlling inflammation in the body, we believed it was also likely miRNAs played a role in the inflammation process that underlies MS,” said Smith. “What we found was important to the understanding of the disease – the profile of expression or activity of miRNAs did change in MS patients as compared to healthy adults.”
What researchers discovered was a negative feedback loop. Specifically, Smith utilized genetic knockout mice to prevent miR-29 from functioning, resulting in unrestrained production of T-bet and interferon gamma (IFN-y). T-bet, a transcription factor, controls the expression of IFN-y, a molecule produced as part of the immune response that is often linked to autoimmune disease when uncontrolled. miR-29b, whose expression is elevated in T cells of patients with multiple sclerosis, regulates T-bet and IFN-y, while at the same time, IFN-y enhances miR-29b expression, creating a novel regulatory feedback loop. Based on these findings, as well as an understanding of miR-29b levels in patients with multiple sclerosis, researchers concluded the feedback loop is dysregulated in multiple sclerosis patients, likely contributing to the chronic inflammation that underlies multiple sclerosis.
This research team also found miR-29b is increased in the infection fighting memory CD4+ T or T helper cells of multiple sclerosis patients, which may cause chronic Th1 inflammation. However, miR-29b levels decrease significantly once these T cells are activated in multiple sclerosis patients, additionally supporting the theory that a dysregulated feedback loop exists. Based on their findings, these researchers concluded miR-29 serves as a novel regulator of Th1 differentiation, adding to the understanding of T cells’ regulatory mechanisms that maintain a balance between protective immunity and autoimmunity.
Researchers involved in the study say they hope their findings will inspire additional research that can help measure the presence of miR-29 across cycles of relapse and remission making it possible to utilize the marker as a predictor of disease.
“We know the earlier we intervene with effective therapy the greater the impact we can have on the course and pace of MS,” said Caroline Whitacre PhD, head of the laboratory and vice president for research at Ohio State. “By creating a diagnostic tool that can predict relapse, MS patients’ number 1 complaint, we can potentially change the way clinicians approach therapeutics and treat these patients.”
Source: News Release
Ohio State University Center for Clinical and Translational Science
September 27, 2012
A University of Adelaide researcher has published results that suggest a possible new mechanism to control multiple sclerosis (MS).
Dr Iain Comerford from the University’s School of Molecular and Biomedical Science earned a three-year fellowship from MS Research Australia to work on this project. It is directed towards understanding how specific enzymes in cells of the immune system regulate immune cell activation and migration.
Along with his colleagues, Professor Shaun McColl and PhD students Wendel Litchfield and Ervin Kara, he focused on a molecule known as PI3Kgamma, which is involved in the activation and movement of white blood cells.
"There’s already been worldwide interest in PI3Kgamma in relation to other human inflammatory disorders, such as diabetes and rheumatoid arthritis, and our study links this molecule and MS," said Dr Comerford, who is a Multiple Sclerosis Research Australia Fellow at the University of Adelaide.
Dr Comerford and his colleagues have now shown that this molecule is crucial for the development of experimental autoimmune encephalitis (EAE) in an animal model developed as a standard laboratory system for studying multiple sclerosis.
The team showed that a genetic alteration, which knocked out that particular molecule, resulted in a high resistance to the development of EAE and therefore protected against the nervous system damage typical of multiple sclerosis.
When the molecule is present, severe damage to the insulating myelin in the central nervous system was evident, resulting in inflammation in the spinal cord and myelin loss.
Following up on this result, the team then used an orally active drug that blocks the activity of the molecule PI3Kgamma at the first signs of disease onset. The drug even suppressed the development of EAE and reversed clinical signs of the disease.
"Our results so far have been very promising," Dr Comerford said.
"We’ve shown that by blocking PI3Kgamma, we can reduce the activation of self-reactive immune cells, reduce the release of inflammation-inducing molecules from immune cells, and also result in a dramatic reduction in the movement of immune cells into the central nervous system.
"Our hope is that future therapies for MS might target this molecule, which could very specifically dampen the damaging inflammation in the central nervous system.
"It will now be crucial to determine whether targeting these molecules could be a safe and effective way to treat MS in humans," Dr Comerford said.
Source: News Release
University of Adelaide
October 4, 2012
A Phase 1 clinical trial led by investigators from the University of California, San Francisco and sponsored by Stem Cells Inc., showed that neural stem cells successfully engrafted into the brains of patients and appear to have produced myelin.
The study, published in the October 10, 2012 issue of Science Translational Medicine, also demonstrated that the neural stem cells were safe in the patients’ brains 1 year post transplant.
The results of the investigation, designed to test safety and preliminary efficacy, are encouraging, said principal investigator David H Rowitch MD PhD, a professor of pediatrics and neurologic surgery at UCSF, chief of neonatology at UCSF Benioff Children’s Hospital, and a Howard Hughes Medical Institute Investigator.
"For the first time, we have evidence that transplanted neural stem cells are able to produce new myelin in patients with a severe myelination disease," said Nalin Gupta MD PhD, associate professor of neurologic surgery and pediatrics and chief of pediatric neurologic surgery at UCSF Benioff Children’s Hospital, and co-principal investigator of the PMD clinical trial.
"We also saw modest gains in neurological function, and while these can’t necessarily be attributed to the intervention because this was an uncontrolled trial with a small number of patients, the findings represent an important first step that strongly supports further testing of this approach as a means to treat the fundamental pathology in the brain of these patients."
In the trial, human neural stem cells developed by Stem Cells, Inc., of Newark, California, were injected directly into the brains of 4 young children with an early-onset, fatal form of a condition known as Pelizaeus-Merzbacher disease (PMD).
In PMD, an inherited genetic defect prevents oligodendrocytes from making myelin. Without myelin sheathing, white matter tracts short-circuit like bare electrical wires and are unable to correctly propagate nerve signals, resulting in neurologic dysfunction and neurodegeneration. Patients with early-onset PMD cannot walk or talk, often have trouble breathing, and undergo progressive neurologic deterioration leading to death between ages 10 and 15. The disease usually occurs in males.
Multiple sclerosis and certain forms of cerebral palsy also involve damage to oligodendrocytes and subsequent demyelination.
Before and after the transplant procedures in the children with PMD, which were conducted between 2010 and 2011, the patients were given standard neurologic examinations and developmental assessments, and underwent MRI. "MRI is the most stringent non-invasive method we have of assessing myelin formation," said Rowitch.
The investigators found evidence that the stem cells had successfully engrafted, receiving blood and nutrients from the surrounding tissue and integrating into the brain, a process that Rowitch likened to "a plant taking root."
This finding was particularly significant, he said, because the cells were not the patients’ own stem cells. "It would have been just as likely to expect that the patients would have rejected them," he said.
The investigators also found indirect evidence that the stem cells had become oligodendrocytes and were producing myelin. "There is no non-invasive way to test this definitively," cautioned Rowitch, "but our MRI findings suggest myelination in the regions that have been transplanted."
Once transplanted and engrafted, neural stem cells have the potential to differentiate into a number of different brain cell types, depending on the area of the brain into which they are inserted. The sites chosen for the Phase1 study were known from animal studies to be the most likely to result in the formation of oligodendrocytes.
In an animal study by another team of investigators, at Oregon Health & Science University’s Papé Family Pediatric Research Institute, published in the same issue ofScience Translational Medicine, Stem Cells Inc’s neural stem cells were injected into mouse models and became oligodendrocytes and formed myelin. "The animal study is consistent with the MRI findings from the clinical trial and further supports the possibility of donor-derived myelination in human patients," said Rowitch.
"This is a landmark study for the field," said Arnold R Kriegstein MD PhD, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. "Without such studies in human patients, we won’t really know how transplanted cells behave — whether they disperse or migrate, whether they engraft or degenerate and die, whether immune-suppressing regimens really work or not. It’s only through these investigations that we will be able to refine the necessary procedures and technologies and make progress toward cell-based therapies for this disease and related disorders."
Co-investigators of the clinical team are Jonathan Strober, MD, Director of Clinical Services for Child Neurology and Director of the Muscular Dystrophy Clinic at UCSF Children’s Hospital, and Nalin Gupta, MD, PhD, Chief of Pediatric Neurological Surgery at UCSF Benioff Children’s Hospital.
The study was sponsored and supported by Stem Cells, Inc.
UCSF staff Tamara Ryan, Rachel Perry, Mary Ulman, and Drs Barkovitch, Henry, Jeremy, and Kang received partial salary support from the sponsor.
Source: News Release
University of California – San Francisco
October 10, 2012
Researchers at Oregon Health & Science University have discovered that blocking a certain enzyme in the brain can help repair the brain damage associated with multiple sclerosis and a range of other neurologic disorders.
The discovery could have major implications for multiple sclerosis, complications from premature birth, and other disorders and diseases caused by demyelination – a process where the insulation-like sheath surrounding nerve cells in the brain becomes damaged or destroyed.
The study was published this week in the online edition of the Annals of Neurology. The study was conducted by a team of researchers led by Larry Sherman PhD, who is a professor of cell and development biology at OHSU and a senior scientist in the Division of Neuroscience at the Oregon National Primate Research Center.
"What this means is that we have identified a whole new target for drugs that might promote repair of the damaged brain in any disorder in which demyelination occurs," Sherman said. "Any kind of therapy that can promote remyelination could be an absolute life-changer for the millions of people suffering from MS and other related disorders."
Sherman’s lab has been studying multiple sclerosis and other conditions where myelin is damaged for more than 14 years. In 2005, he and his research team discovered that a sugar molecule, called hyaluronic acid, accumulates in areas of damage in the brains of humans and animals with demyelinating brain and spinal cord lesions. Their findings at the time, published in Nature Medicine, suggested that hyaluronic acid itself prevented remyelination by preventing cells that form myelin from differentiating in areas of brain damage.
The new study shows that the hyaluronic acid itself does not prevent the differentiation of myelin-forming cells. Rather, breakdown products generated by a specific enzyme that chews up hyaluronic acid – called a hyaluronidase – contribute to the remyelination failure.
This enzyme is highly elevated in multiple sclerosis patient brain lesions and in the nervous systems of animals with an multiple sclerosis-like disease. The research team, which included OHSU pediatric neurologist Stephen Back MD and OHSU neuroscientist Steve Matsumoto PhD, found that by blocking hyaluronidase activity, they could promote myelin-forming cell differentiation and remyelination in the mice with the multiple sclerosis-like disease. Most significantly, the drug that blocked hyaluronidase activity led to improved nerve cell function.
The next step is to develop drugs that specifically target this enzyme. “The drugs we used in this study could not be used to treat patients because of the serious side effects they might cause,” said Sherman. “If we can block the specific enzyme that is contributing to remyelination failure in the nervous system, it would likely cause few, if any, side effects.”
Sherman and other researchers at the ONPRC are uniquely positioned to test newly developed drugs for their safety and effectiveness in nonhuman primates at ONPRC that spontaneously develop an multiple sclerosis-like disease. If they find a drug that is effective in these monkeys, they will be in a good position to test such drugs in patients.
Sherman cautioned that the discovery does not necessarily signal a cure for multiple sclerosis. Many other factors can contribute to the problems associated with multiple sclerosis and other demyelinating diseases, he said. But discovering the actions of this enzyme — and finding a way to block it — "could at the very least lead to new ways to promote the repair of brain and spinal cord damage either by targeting this enzyme alone or by inhibiting the enzyme in conjunction with other therapies.”
The research was supported by grants from the National Institutes of Health, Fast Forward, LLC (a subsidiary of the National Multiple Sclerosis Society), the Laura Fund for Multiple Sclerosis Research, the March of Dimes Birth Defects Foundation, and the American Heart Association.
Source: News Release
Oregon Health & Science University
October 31, 2012