Multiple sclerosis is a debilitating condition that involves the degeneration of myelin—the fatty tissue that insulates nerve fibers and helps them to conduct impulses. This process, called demyelination, can lead to deficits in sensation, movement and thought processes, depending on exactly which nerve fibers are affected. Replacing lost myelin is a promising approach for treating multiple sclerosis and related diseases, but the mechanisms underlying demyelination and remyelination remain poorly understood.
In research that opens up an encouraging avenue for the development of new treatments, Naoyuki Taniguchi and colleagues from the RIKEN–Max Planck Joint Research Center for Systems Chemical Biology have shown that remyelination is inhibited by sugar molecules called branched O-mannosyl glycans.
Taniguchi and his colleagues genetically engineered a strain of mice carrying mutations in the gene encoding an enzyme called N-acetylglucosaminyltransferase-IX (GnT-IX), which catalyzes the branching of O-mannosyl glycan sugars on proteins in the brain. Using these mice, the researchers found that GnT-IX acts on a specific brain protein called receptor protein tyrosine phosphatase ? (RPTP?), which has previously been shown to play a critical role in demyelination.
Next, the research team fed normal and mutant mice a diet containing the neurotoxin cuprizone, which normally induces demyelination. Over the course of eight weeks, the normal mice were found to have experienced gradual demyelination of the corpus callosum—a major tract of white matter connecting the two hemispheres of the brain. By contrast, although myelin in the corpus callosum had degraded by four weeks in the mutants, myelination had markedly increased by the eight-week mark, suggesting that the defect in the GnT-IX gene enhanced remyelination.
Further experiments revealed that cuprizone treatment can activate non-neuronal cells called astrocytes into a disease state, which leads them to express RPTP? containing branched O-mannosyl glycans. In wild-type mice, activated astrocytes express these branched O-mannosyl glycan molecules, which inhibit remyelination. In mice with a defective GnT-IX gene, however, astrocytes are rarely activated, and the absence of the branched O-mannosyl glycans allows the differentiation of myelin cells and the remyelination of nerve fibers in the corpus callosum.
"We would like to unveil the molecular mechanism by which branched O-mannosyl glycan activates astrocytes," says Taniguchi. "Understanding the underlying mechanism is important for developing a drug to treat multiple sclerosis."
The team next plans to screen for a GnT-IX inhibitor that attenuates astrocyte activation. "The difficult thing is that the drug has to pass through the blood–brain barrier, so collaboration with clinicians will be important," Taniguchi notes.
Primary Source: Kanekiyo, K., et al. Loss of branched O-mannosyl glycans in astrocytes accelerates remyelination, The Journal of Neuroscience 33, 10037–10047 (2013). dx.doi.org/10.1523/JNEUROSCI.3137-12.2013
Source: MedicalXpress © Medical Xpress 2011-2013 (04/10/13)
Scientists from ENDECE Neural presented preclinical data today showing that the company’s lead compound, NDC-1308, addresses one of the root causes of multiple sclerosis (MS) by significantly inducing remyelination in nerves that have been damaged by MS. In an oral presentation at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Copenhagen, Denmark, the ENDECE Neural researchers also reported a dramatic upregulation of genes in signaling pathways involved in myelin sheath production.
NDC-1308 works by inducing differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes, cells that synthesize and maintain the myelin sheath that covers nerves in the brain and spinal cord, the researchers noted. By contrast, the female hormones estradiol and estriol do not exert that effect.
“Repair of the myelin sheath, called remyelination, has long been an elusive goal in the treatment of multiple sclerosis,” explained Steven Nye, Ph.D., Vice President of Discovery at ENDECE Neural. “The synthesis of NDC-1308, an estradiol analog, was inspired by observations that pregnant women typically do not experience the symptoms of MS during the third trimester. In our experiments, NDC-1308 induces remyelination in animal models of demyelination, compared to estradiol and estriol which appear to be neuroprotective but do not induce OPC differentiation.”
In his presentation, Dr. Nye described how he and his colleagues synthesized more than 40 proprietary estradiol analogs in which the core structure of estradiol had been modified, and assessed how subsets of those modifications changed the hormone’s biological activity. The researchers identified NDC-1308 as the most potent of several proprietary analogs having the ability to directly induce differentiation of OPCs into mature oligodendrocytes. NDC-1308 derives its novel biological activity from the addition of a specific alkoxyalklyl moiety to the C-6 position on the estradiol B-ring.
Dr. Nye reported the following findings:
- A 20% increase in remyelination (compared to vehicle control) of hippocampal regions of the brain (P<0.01) was associated with a 2-week course of NDC-1308 (50 mg/Kg once daily) in a mouse model of demyelination, in which the neurotoxicant cuprizone was used to remove the myelin sheath from the axons (nerve fibers) of mice.
- NDC-1308 caused a dramatic upregulation of key genes (5- to 75-fold) in signaling pathways involved in OPC differentiation and myelin sheath production.
- NDC-1308 significantly induced OPCs to differentiate into mature oligodendrocytes (P<0.05).
- NDC-1308 (3 μM/day for 4 days) enhanced remyelination in demyelinated rat brain slices visualized by staining for myelin basic protein, which was consistent with the mouse cuprizone data.
Prophylactic administration of NDC-1308 (10 mg/kg/day for 10 days) delayed the onset of MS symptoms and reduced the severity of MS in a mouse model of experimental allergic encephalitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG), suggesting that the compound may play a dual remyelination/anti-inflammatory role in treating MS. “Despite its structural similarity to estradiol and estriol, NDC-1308 differs from those two female hormones by virtue of its potent induction of remyelination, as demonstrated in animal models of MS,” commented James G. Yarger, Ph.D., chief executive officer and co-founder of ENDECE Neural. “Unlike estradiol and estriol, NDC-1308 induces OPC differentiation and maturation of oligodendrocytes. We envision administration of NDC-1308 either alone or in combination with current therapeutics that target the immune response and/or inflammation associated with MS. NDC-1308 may thus fill an unmet medical need for a remyelinating therapy in MS, one that may help improve the lives of patients living with this devastating neurological disease.”
NDC-1308 is a novel chemical entity designed to address one of the root causes of MS, and is being developed for potential use either alone or in combination with other MS therapeutics that slow the progression of the disease. By controlling key genes in pathways leading to myelin synthesis, NDC-1308 appears to induce restoration of the lost myelin sheath that is believed to cause the devastating symptoms of MS. NDC-1308 is a small molecule that readily crosses the blood-brain barrier, allowing it to reach the tissues in the brain and spinal cord where promoting myelin production is needed. ENDECE Neural discovered NDC-1308, and owns the intellectual property surrounding the compound.
Source: Rock Hill Herald Online © Rock Hill Herald Online (04/10/13)
A groundbreaking study in multiple sclerosis focusing on “remyelination in the brain” has been initiated by Omar Khan, M.D., professor and chair of neurology at the Wayne State University School of Medicine.
“This is a novel approach in the treatment of multiple sclerosis, which is characterized by diffuse demyelination and axonal loss in the central nervous system,” said Dr. Khan, who also serves as director of the Multiple Sclerosis Center and director of the Sastry Foundation Advanced Imaging Laboratory. “In this study, we are targeting remyelination in the central nervous system.”
Dr. Khan noted that there are 10 United States Food and Drug Administration-approved treatments for multiple sclerosis, none with any well-characterized reparative or remyelinating potential. Those treatments primarily focus on altering the behavior of the immune system and target inflammation.
However, this new approach targets remyelination in the central nervous system using a humanized monoclonal antibody that binds to the semaphorin 4D, a member of the semaphorin family of proteins and an important mediator of axonal growth cone guidance. Semaphorin-induced signaling also has been shown to induce growth cone collapse of neurons and apoptosis of neural precursors, and to induce process extension collapse and apoptosis of oligodendrocytes. Semaphorins consist of a family of soluble and membrane-bound proteins that were originally defined as axonal-guidance factors. These proteins play important roles in establishing precise connections between neurons and their appropriate targets.
“Therefore, it is a plausible target with the realistic goal of achieving remyelination,” Dr. Khan said. “This is a paradigm shift and the start of the next generation of therapies to treat multiple sclerosis that will change its focus to repair rather than inflammation.”
The brain can largely 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 muscles. The white parts of the brain are white because a cell type called oligodendrocytes makes a cholesterol-rich membrane called myelin that coats the axons.
The myelin’s function is to insulate the axons, similar to the plastic sheath coating electrical cables. In addition, the myelin speeds communication along axons and makes that communication more reliable. In patients with MS, their immune system attacks the myelin sheathing. The subsequent degradation leads to the messages from the brain to other parts of the body leaking and derailing from their intended target.
Restoring the myelin sheathing is the goal of Dr. Khan’s new study.
The Wayne State University Multiple Sclerosis Center, in collaboration with Vaccinex, a privately-held biotechnology company headquartered in Rochester, N. Y., initiated this early stage dose-defining study.
“If successful, this will lead to large scale studies with this molecule targeting remyelination in the brain as a primary focus, detected by advanced imaging techniques such as magnetization transfer ratio,” Dr. Khan said. “The real challenge will be to reverse or reduce conduction blocks in the demyelinated nerve that may translate into neurologic improvement. If we could achieve that with this approach, it opens the door for hundreds of thousands of multiple sclerosis patients for whom no therapy is currently effective. This may also provide a unique opportunity in combining therapies with different mechanistic approaches.”
WSU is home to the only MS center in Michigan and among the 10 sites in the world undertaking this translational initiative. The center is among the top five MS centers in the U. S., with more than 4,000 patients. The center is involved in cutting-edge immunologic, genetic, MR imaging and therapeutic studies.
Dr. Khan said only three molecules in the world, including this monoclonal antibody, are being investigated in patients with multiple sclerosis that focus on remyelination. “It is humbling to lead such a unique groundbreaking effort and that Wayne State University is one of the few centers in the world that are participating in this next true generation translational research,” he said. “The patients are observed over night at Harper University Hospital, which has been a great partner in facilitating this research endeavor.”
Multiple sclerosis affects more than 500,000 people (or one in 600) in the U.S. and more than 2 million worldwide. After trauma, it is the most common cause of disability in young adults. While there is no cure, several treatments are approved for the relapsing form of multiple sclerosis that reduces the frequency of flare-ups and slows disease progression.
This study was funded by Vaccinex.
Source: Newswise ©2013 Newswise, Inc (19/09/13)
University of Chicago researchers awarded NIH grant to develop novel multiple sclerosis treatment(18/09/13)
Researchers from the University of Chicago have been awarded a five-year, $1.5 million grant from the National Institutes of Health (NIH) to develop stimulated dendritic cell-derived exosomes that show remarkable promise as a treatment for multiple sclerosis and other neurological diseases involving loss of myelin, the insulation around nerve fibers.
Exosomes produced in the blood appear to play a causal role in the protective effects of regular exercise and learning, collectively known as "environmental enrichment," on the brain. These exosomes contain specific microRNAs that promote myelination of aging brain as well as brain damaged by multiple sclerosis modeled in animal brain tissues.
Based on this discovery, the Kraig lab is currently exploring the possibility of using cultured dendritic cells to recreate this effect. To do so will open new research opportunities for treatment of disorders that occur with a loss of myelin.
Led by Richard Kraig, MD, PhD, the William D. Mabie Professor in the Neurosciences in the department of Neurology at the University of Chicago, the research project is part of the Extracellular RNA Communication program, which aims to better understand extracellular RNA. This new initiative is supported by the NIH Common Fund, which funds high-impact, trans-NIH projects that have the potential to dramatically affect biomedical research over the next decade.
The Kraig project focuses on exosomes-small lipid vesicles that carry protein, RNA, and importantly, non-coding, extracellular microRNA, which are thought to enable cell-to-cell communication throughout the body.
Kraig and his team, which includes Aya Pusic and Kae Pusic, PhD, discovered that dendritic cells, professional antigen presenting cells of the immune system, can be stimulated by factors released during environmental enrichment to produce exosomes containing microRNAs that improve brain health.
When applied to cultured brain tissue or administered nasally to live animals, these dendritic cell-derived exosomes significantly increased baseline levels of myelin-the protective sheath around neurons, which is damaged in multiple sclerosis. Importantly, exosome administration also improved the recovery of demyelinated nerve cells, which serve as a model for multiple sclerosis.
"All evidence suggests these exosomes can be crafted into a novel therapy to treat multiple sclerosis," Kraig said. "The NIH Common Fund grant allows us to pursue the development of this promising discovery, while simultaneously characterizing its basic mechanisms."
Dendritic cell-derived exosomes have no known toxic effects, can cross the blood-brain barrier without use of an additional delivery vehicle and are scalable for mass production through laboratory-cultured dendritic cells. These traits make them an extremely promising treatment for multiple sclerosis and many other neurodegenerative diseases that involve loss of myelination, such as traumatic brain injury. They may also be useful in slowing the degradation that occurs with normal aging.
The Kraig lab will investigate the underlying biological mechanisms and functions of the extracellular microRNAs contained in stimulated dendritic cell-derived exosomes. In addition, the team will study a promising link between these exosomes, reduced oxidative stress and increased antioxidant levels seen in treated brains, effects they hope also will lead to potential therapeutics for neurological diseases.
"We believe that we have identified a naturally occurring mechanism by which increased exercise and learning improves brain health through myelination," said Kraig. "Importantly, we have also discovered a way to mimic this nutritive effect through the use of cultured dendritic cell-derived exosomes containing specific microRNAs."
Source: News-Medical.Net (18/09/13)
Scientists from ENDECE Neural presented pre-clinical data this week showing that the company's lead compound, NDC-1308, can address one of the root causes of multiple sclerosis (MS) by inducing remyelination (restoration of the lost myelin sheath in nerves that have been damaged by MS). The results, which were presented at the CNS Diseases World Summit 2013 in Boston, suggest that NDC-1308 can induce remyelination in an animal model of demyelination, in which the neurotoxicant cuprizone was used to remove the myelin sheath from the axons (nerve fibers) of mice.
According to the researchers, NDC-1308 induces differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (cells that synthesize and maintain the myelin sheath that covers nerves in the brain and spinal cord).
"For decades, researchers have been seeking ways to induce remyelination in diseases such as MS that are characterized by demyelination," noted James G. Yarger, Ph.D., chief executive officer and co-founder of ENDECE Neural. "Observations that pregnant women typically do not experience the symptoms of MS during the third trimester have led researchers to investigate various forms of synthetic estrogen for the treatment of MS. Our research shows that the estradiol analog NDC-1308 can induce remyelination in demyelinated axons in a cuprizone animal model of demyelination."
In their poster presentation, Dr. Yarger and colleagues described how they synthesized more than 40 proprietary estradiol analogs in which the core structure of estradiol had been modified, and assessed how those modifications changed the hormone's biological activity. NDC-1308 was identified as the most potent of several proprietary analogs having the ability to directly induce differentiation of OPCs into mature oligodendrocytes. By contrast, the female hormones estradiol and estriol do not exhibit that activity. The investigators reported the following findings:
-- In a cuprizone mouse model of demyelination, a 2-week course of NDC-1308 (50 mg/Kg once daily) was associated with a 20% increase in remyelination of hippocampal regions of the brain (P<0.01) in proof-of-concept studies.
-- Consistent with the mouse cuprizone data, NDC-1308 enhanced remyelination in demyelinated rat brain slices in culture visualized by staining for myelin basic protein.
-- NDC-1308 induced isolated OPCs to differentiate into mature oligodendrocytes in culture, whereas estriol and estradiol did not (P<0.01).
-- NDC-1308 caused a dramatic upregulation of genes (5- to 75-fold) in signaling pathways involved in OPC differentiation and myelin sheath production.
"While NDC-1308 is structurally similar to estradiol and estriol, it differs from those two female hormones in that it potently promotes remyelination by inducing OPC differentiation and maturation of oligodendrocytes at the sites of demyelination," explained co-investigator Bruce D. Trapp, Ph.D., who is chair of the Department of Neurosciences at the Lerner Research Institute at the Cleveland Clinic. "NDC-1308 induces significant remyelination of axons in the demyelination model in mice."
"There is a large market opportunity for NDC-1308, as no commercially available drug is capable of directly restoring the lost myelin sheath on damaged axons in patients with MS," added Dr. Yarger. "Dependent on the outcome of clinical studies, we envision NDC-1308 being administered either alone or in combination with current therapeutics that target the immune response and/or inflammation associated with MS. By inducing remyelination, it may be possible to restore muscle control, mobility, and cognition in patients with MS. Therefore, a drug that induces remyelination, such as NDC-1308, could potentially double the size of the current market for MS therapeutics."
NDC-1308 is a novel chemical entity designed to address one of the root causes of MS, and is being developed for potential use either alone or in combination with other MS therapeutics that slow the progression of the disease. By controlling key genes in pathways leading to myelin synthesis, NDC-1308 appears to induce restoration of the lost myelin sheath that is believed to cause the devastating symptoms of MS. NDC-1308 is a small molecule that readily crosses the blood-brain barrier, allowing it to reach the tissues in the brain and spinal cord where promoting myelin production is needed. ENDECE Neural discovered NDC-1308 in-house, and owns the intellectual property surrounding the compound.
Source: Market Watch Copyright © 2013 MarketWatch, Inc (10/09/13)
Sleep may play a key role in the production and repair of myelin, the protective covering of nerve cells that is attacked and damaged in people with multiple sclerosis, according to early research in mice carried out at the University of Wisconsin.
The research found that the rate of production of a type of brain cell called oligodendrocyte precursor cells (OPCs) doubled in sleep relative to waking. OPCs are a type of cell that give rise to myelin in both healthy and injured adult brains.
“OPCs are among the few brain cells that in an adult brain keep proliferating and dividing and producing more cells,” said Dr. Chiara Cirelli, a professor in the department of psychiatry at the University of Wisconsin and senior author on the paper, which was published online Sept. 4 in The Journal of Neuroscience. “Most all neurons in the adult brain don’t do that—that’s why people are studying them now quite extensively.”
Cirelli began studying the functions of sleep about 15 years ago, by looking at all the genes that change in an animal’s brain during sleep versus waking. In a 2004 study in the journal Neuron, her research group found that up to five percent of genes expressed in the cortex or "gray matter" of the brain change solely due to whether an animal is asleep or awake.
In the current study, they looked specifically at OPCs, a type of glial cell. Glial cells are all the brain cells that are not neurons, and used to be thought of as simply the "glue" of the brain, whose only function was to support the neurons. Now, the glia, which have been discovered to help maintain the brain’s internal equilibrium and produce myelin (among other functions), are the subject of intense scientific focus.
In Cirelli’s current research, sleep triggered genes produced OPCs, while sleep deprivation led to a suppression of these genes and more activity in genes that have been implicated in cell death and stress responses.
The findings suggest that chronic sleep loss could aggravate symptoms of diseases like MS which involve damage to myelin, Cirelli said, but there is a lot more work to be done before any firm conclusions can be drawn in people.
“Disturbed sleep may aggravate perhaps the symptoms of the disease, in a vicious cycle,” she said. “It would be nice to try to block the vicious cycle and improve the quality of sleep in these patients.”
Multiple sclerosis, which affects 400,000 people in the United States and has no cure, is a disease in which the body’s own immune system attacks the myelin surrounding nerves and can cause numbness, paralysis and loss of vision.
In Cirelli’s study, the rate of OPC production was particularly high during rapid eye movement (REM) sleep, which the researchers determined using brain wave measurements in sleeping mice. REM sleep, which is when people typically dream, occurs at the tail end of a regular sleep cycle.
“What this means, we don’t know,” Cirelli said, “but there might be hormonal changes in non-REM versus REM sleep.”
For example, in older adults prolactin (a hormone which regulates the immune system and is involved in nursing) is released during REM sleep, and studies in pregnant women have shown that as prolactin increases, symptoms of MS decrease.
“This is just speculation, though,” Cirelli points out. She hopes that other researchers will take up the study of sleep and OPCs in MS.
“It would be nice if someone could follow up and just look to see if there is any indication if the symptoms of the disease are aggravated during periods of especially severe sleep deprivation,” she said.
Her research group plans to study the effect of sleep on gene activation in other glial cells, called astrocytes.
Source: cleveland.com © 2013 Northeast Ohio Media Group LLC (06/09/13)
New treatments that could help slow the progression of multiple sclerosis could be a step closer due to research by Edinburgh University.
In MS patients the protective layer around nerve cells in the brain, known as myelin, is broken down.
Scientists have discovered that immune cells, known as macrophages, help trigger the regeneration of myelin.
The researchers hope their work could eventually lead to the development of new drugs.
The sheath around nerves cells, made of myelin, is destroyed in MS, leaving the nerves struggling to pass on messages.
This leads to problems with mobility, balance and vision. There is no cure but current treatments concentrate on limiting the damage to myelin.
Now the team at Edinburgh University has found that the immune cells, known as macrophages, can release a compound called activin-A, which activates production of more myelin.
Dr Veronique Miron, from the Medical Research Council Centre for Regenerative Medicine at the university, said: "In multiple sclerosis patients, the protective layer surrounding nerve fibres is stripped away and the nerves are exposed and damaged.
"Approved therapies for multiple sclerosis work by reducing the initial myelin injury - they do not promote myelin regeneration.
"This study could help find new drug targets to enhance myelin regeneration and help to restore lost function in patients with multiple sclerosis."
The study, which looked at myelin regeneration in human tissue samples and in mice, was funded by the MS Society, the Wellcome Trust and the Multiple Sclerosis Society of Canada.
The findings are published in Nature Neuroscience.
Scientists now plan to start further research to look at how activin-A works and whether its effects can be enhanced.
Dr Susan Kohlhaas, head of biomedical research at the MS Society, said: "We urgently need therapies that can help slow the progression of MS and so we're delighted researchers have identified a new, potential way to repair damage to myelin.
"We look forward to seeing this research develop further."
Source: BBC News © British Broadcasting Corporation 2013 (22/07/13)
The Myelin Repair Foundation (MRF) today has granted a non-exclusive sublicense to Biogen Idec for the use of MRF's technologies to generate a novel mouse model for all demyelinating diseases, including multiple sclerosis (MS). Biogen Idec, an independent biotechnology company with a strong focus on multiple sclerosis therapies, will use the MRF technology in its in-house drug discovery programs. The Myelin Repair Foundation and Biogen Idec will collaborate to improve the licensed technologies to enhance discovery of myelin repair therapeutics and speed clinical development.
Novel technologies such as this mouse model come as a direct result of MRF's Accelerated Research Collaboration™ (ARC™) model, which centers on a collaborative research approach that accounts for the entire continuum of therapeutics development, from early research through clinical trials. The DTA mouse model was pioneered by MRF Principal Investigator Dr. Brian Popko, Ph.D., and Dr. Maria Traka, Ph.D., both from the University of Chicago, in collaboration with MRF Principal Investigator Dr. Stephen Miller, Ph.D. and Dr. Joseph Podojil, Ph.D., both from Northwestern University. The most commonly used models for MS currently mimic the hyperactive inflammatory process in MS patients. The DTA model is unique because demyelination is the result of the specific loss of the principal target cells in multiple sclerosis, thus facilitating the identification of potential treatments that will restore myelin production by these target cells.
“Our collaboration with the Myelin Repair Foundation will incorporate their technology into our evaluation of novel approaches to stimulating myelin repair,”? said Ken Rhodes, Vice President of Neurology Research, Biogen Idec. “Our collaborative efforts with MRF scientists will evaluate drug candidates' effectiveness in reversing myelin damage and hopefully advance R&D efforts for a new generation of MS therapeutics.”?
“We are thrilled to collaborate with Biogen Idec as a demonstration of our commitment to patients,”? said Scott Johnson, CEO, founder and president of the Myelin Repair Foundation. “We feel it is unique that as a nonprofit research organization, we are licensing our technology to a pharmaceutical company to support drug discovery of MS therapeutics. The MRF's Accelerated Research Collaboration model is designed to translate academic research discoveries to the industry setting. With Biogen Idec by our side, our goal is to utilize improved technology to advance MRF programs for myelin repair therapies into the clinic, to ultimately impact patients with MS.”?
The DTA model displays characteristics reminiscent of the progressive form of MS, not yet available in any other mouse model. The DTA mouse model is designed to facilitate the discovery of drugs for MS and other demyelinating diseases. Currently, there are no treatments on the market to repair myelin damage from MS. This chronic disease is typically due to active degeneration of the myelin sheath surrounding the nerves and inadequate repair of the damage.
Source: Myelin Repair Foundation (02/07/13)
A skin patch delivering peptides derived from the presumed autoimmune target in multiple sclerosis reduced relapse frequency and brain lesions in a pilot clinical trial, researchers said.
In 30 patients with relapsing-remitting MS enrolled in the 1-year, placebo-controlled trial, those receiving the myelin skin patches containing 1 mg of peptides had an annualized relapse rate of 0.43 versus 1.4 in patients treated with a placebo patch (P=0.007), according to Krzysztof Selmaj, MD, PhD, of the Medical University of Lodz in Poland, and colleagues.
The mean cumulative number of gadolinium-enhancing brain lesions per patient was lower with the 1 mg patch by 66.5% compared with controls (0.0085 versus 0.0255, P=0.02), they reported online in JAMA Neurology.
However, a 10-mg patch appeared to be substantially less effective than the lower-dose patch. Brain lesion counts and volumes in this group (which had only four patients) were similar to those in the placebo group, even as the mean annualized relapse rate was lower at 0.25 than in either of the other two treatment arms (P not reported).
Selmaj and colleagues speculated that the higher peptide dose in the 10-mg patch may have triggered increased pathological immune cell activity, potentially "inducing a number of specific T cells to differentiate into effector cells," they wrote.
No serious adverse events were reported. Patch-site reactions of "modest intensity" were seen in four of the 20 patients receiving the myelin patches. Other adverse effects occurred at similar rates in all three arms.
In an accompanying commentary, Lawrence Steinman, MD, of Stanford University, called the results "promising" and added that they were consistent with what many in the field have considered the Holy Grail in MS: the induction of immunological tolerance.
MS is widely believed to result from an autoimmune attack on myelin, the principal component of the sheathing that surrounds nerve fibers. When the myelin sheaths become sufficiently degraded, nerve function is impaired as well.
But, compared with the drug-development effort industry has expended toward agents that interfere with some aspect of immune function, comparatively little has focused on persuading the immune system to stop attacking myelin in the first place, Steinman indicated.
"It is clear that the pharmaceutical industry is taking the safer approach, the 'well-traveled road,' when they redirect drugs with a major impact on immune function, drugs often already approved for other diseases," he wrote, alluding to drugs such as anti-CD20 drugs including rituximab (Rituxan) and ocrelizumab and the anti-CD52 agent alemtuzumab (Lemtrada).
Hitting those targets "results in massive perturbation and deletion of major components of the immune system, an approach well worth taking in malignancy, but an approach that could prove problematic in the long run for chronic autoimmune diseases of the nervous system," Steinman wrote.
In the current study, Selmaj and colleagues selected three myelin-based peptides (without industry funding or participation) that could be delivered transdermally from patches placed on the upper arm. These peptides included epitopes that earlier studies had suggested were targeted for immune attack in MS patients.
The patches were formulated to deliver 1 or 10 mg of these peptides or saline -- 10 patients received the saline patches, 16 the 1-mg patch, and four the 10-mg patch. The patches were changed weekly during the first 4 weeks and then monthly for 11 months. Patients and clinical staff were blinded to treatment assignments; the patches were visually identical.
Reflecting the clinical MS population, most patients were women. The mean age was about 37, with duration of MS symptoms averaging about 8 years and baseline EDSS disability scores averaging 2.6. Mean annualized relapse rate prior to enrollment was 1.1.
After one year in the study, the number of relapse-free patients and the number showing disability progression in each treatment group were as follows:
Placebo: relapse free, 1/10; progressive disability, 7/10
1 mg myelin: relapse free, 10/16; progressive disability, 3/16
10 mg myelin: relapse free, 3/4; progressive disability, 1/4
Mean EDSS scores increased by 0.75 in the placebo group versus 0.08 and 0.00 in the 1- and 10-mg patch groups, respectively.
MRI results showed a more mixed picture, especially with respect to the 10-mg group. The mean cumulative number of gadolinium-enhancing lesions with 10 mg was actually higher than in the placebo group (0.0341 versus 0.0255), and the volume of those lesions was nearly doubled with the 10-mg patch versus placebo.
But the mean cumulative number of new T2 lesions was lower with both the 1- and 10-mg patches (0.75 and 1.25, respectively) than in the placebo group (2.4).
Mean T1 lesion volume decreased in both of the myelin patch arms whereas it increased with placebo, yet mean T2 lesion volume decreased only with the 1-mg patch.
Overall, Selmaj and colleagues concluded that "the efficacy and safety profiles that have emerged from this study make the transdermal application of a mixture of three myelin peptides, an attractive and promising therapeutic approach in patients with relapsing-remitting MS."
And, in line with Steinman's cautions about untoward immune effects of other treatment strategies, Selmaj and colleagues suggested that myelin peptide delivery would "spar[e] other mechanisms critical for immune protection."
Steinman suggested that the same approach could also yield good results in other neuroimmunological diseases thought to have single-antigen autoimmune targets -- specifically, neuromyelitis optica and myasthenia gravis. The self-antigen damaged in the former is aquaporin 4, while in the latter it's the acetylcholine receptor molecule
The study had no external funding.
Selmaj and colleagues reported relationships with Novartis, Biogen Idec, ONO Pharma, Genzyme, Roche, Synthon, Teva, and Merck Serono.
Steinman reported serving as founder of a company, Tolerion, aimed at developing antigen-specific tolerance therapies.
Source: Medpage Today © 2013 MedPage Today, LLC (02/07/13)
Exotic fish could hold the key to the development of new treatments for diseases like multiple sclerosis, Scottish scientists claim.
A study into the nervous systems of exotic fish could offer insights into the disease which is caused by a breakdown of the vital nerve sheath, myelin.
Researchers at the University of Edinburgh say they have uncovered ‘vital clues’ in the brains of zebrafish - tropical fish of the minnow family - about the way that organisms produce the fatty sheath that insulates and protects nerve fibres.
They say fresh insights gained from the study could help understanding of how the nervous system works.
Myelin is critical for allowing nerve impulses to be transmitted quickly, enabling the human body to carry out a range of everyday functions such as walking, speaking and seeing.
The scientists found that individual cells in the brain and central nervous system have only a very short time period in which to generate this protective coating.
It is the first time that scientists have been able to quantify the time frame, which is only a matter of hours.
They hope that the results of their studies may one day help the treatment of myelin-related conditions such as multiple sclerosis.
The researchers are now studying how manipulation of genes and the use of drugs might promote myelin formation in zebrafish.
Myelin - which is made by specialised cells called oligodendrocytes - is crucial for good health.
When myelin breaks down, and is not repaired properly, it can cause numbness, loss of vision and dizziness. It also leads to the debilitating symptoms of diseases such as MS.
Although MS patients have an abundance of oligodendrocytes in their brains, these fail to produce sufficient myelin to bring about repair.
The Edinburgh team used zebrafish in the study because they share more than 80 per cent of the genes associated with human diseases.
The tiny fish also exhibit responses to drugs that are very similar to those of humans.
Young zebrafish are transparent, which allows researchers to look directly into their living nervous system without surgical or physical intervention.
Dr David Lyons, of the university’s Centre for Neuroregeneration, said: ‘To enhance myelin repair, we will need to improve either MS patients’ ability to make myelin during the short time in which they have to do this, or find a way to allow them to produce myelin for a longer period of time.’
The study, which is published in Developmental Cell, was carried out in the Centre for Neuroregeneration in collaboration with the MRC Centre for Regenerative Medicine at the University of Edinburgh.
Source: The Daily Mail © Associated Newspapers Ltd 2013 (25/06/13)
A phase 1 clinical trial for the first treatment to reset the immune system of multiple sclerosis (MS) patients showed the therapy was safe and dramatically reduced patients’ immune systems’ reactivity to myelin by 50 to 75 percent, according to new Northwestern Medicine research.
In MS, the immune system attacks and destroys myelin, the insulating layer that forms around nerves in the spinal cord, brain and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness.
“The therapy stops autoimmune responses that are already activated and prevents the activation of new autoimmune cells,” said Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “Our approach leaves the function of the normal immune system intact. That’s the holy grail.”
Miller is the co-senior author of a paper on the study, which was published June 5 in the journal Science Translational Medicine. The study is a collaboration between Northwestern’s Feinberg School, University Hospital Zurich in Switzerland and University Medical Center Hamburg-Eppendorf in Germany.
The human trial is the translation of more than 30 years of preclinical research in Miller's lab.
In the trial, the MS patients’ own specially processed white blood cells were used to stealthily deliver billions of myelin antigens into their bodies so their immune systems would recognize them as harmless and develop tolerance to them.
Current therapies for MS suppress the entire immune system, making patients more susceptible to everyday infections and higher rates of cancer.
While the trial’s nine patients -- who were treated in Hamburg, Germany -- were too few to statistically determine the treatment’s ability to prevent the progression of MS, the study did show patients who received the highest dose of white blood cells had the greatest reduction in myelin reactivity.
The primary aim of the study was to demonstrate the treatment’s safety and tolerability. It showed the intravenous injection of up to 3 billion white blood cells with myelin antigens caused no adverse affects in MS patients. Most importantly, it did not reactivate the patients’ disease and did not affect their healthy immunity to real pathogens.
As part of the study, researchers tested patients’ immunity to tetanus because all had received tetanus shots in their lifetime. One month after the treatment, their immune responses to tetanus remained strong, showing the treatment’s immune effect was specific only to myelin.
The human safety study sets the stage for a phase 2 trial to see if the new treatment can prevent the progression of MS in humans. Scientists are currently trying to raise $1.5 million to launch the trial, which has already been approved in Switzerland. Miller’s preclinical research demonstrated the treatment stopped the progression of relapsing-remitting MS in mice.
“In the phase 2 trial we want to treat patients as early as possible in the disease before they have paralysis due to myelin damage.” Miller said. “Once the myelin is destroyed, it’s hard to repair that.”
In the trial, patients’ white blood cells were filtered out, specially processed and coupled with myelin antigens by a complex GMP manufacturing process developed by the study co-senior authors, Roland Martin, Mireia Sospedra, and Andreas Lutterotti and their team at the University Medical Center Hamburg-Eppendorf. Then billions of these dead cells secretly carrying the myelin antigens were injected intravenously into the patients. The cells entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. During this process, the immune cells start to recognize myelin as a harmless and immune tolerance quickly develops. This was confirmed in the patients by immune assays developed and carried out by the research team in Hamburg.
This therapy, with further testing, may be useful for treating not only MS but also a host of other autoimmune and allergic diseases simply by switching the antigens attached to the cells. Previously published preclinical research by Miller showed the therapy’s effectiveness for type 1 diabetes and airway allergy (asthma) and peanut allergy.
The MS human trial relates directly to Miller’s recently published research in mice in which he used nanoparticles -- rather than a patient’s white blood cells -- to deliver the myelin antigen. Using a patient’s white blood cells is a costly and labor-intensive procedure. Miller’s study showed the nanoparticles, which are potentially cheaper and more accessible to a general population, could be as effective as the white blood cells as delivery vehicles. This nanoparticle technology has been licensed to Cour Pharmaceutical Development Company and is in preclinical development.
Miller’s research represents several pillars of Northwestern’s Strategic Plan by discovering new ways to treat disease in the biomedical sciences and translating those discoveries into ideas and products that make the world a better place for everyone.
The research was supported by the German Federal Ministry for Education and Research and the Cumming Foundation.
Source: Northwestern University (11/06/13)
Doctors hope a new experimental treatment could halt the progression of multiple sclerosis.
For the first time, researchers have reprogrammed the immune systems of MS patients to stop cells attacking the protective layer around nerves in the spinal cord.
The destruction of the insulating sheath - called myelin - prevents normal transmission of nerve signals, triggering symptoms of the disease such as limb paralysis.
The clinical trial showed that patients' immune systems learned to recognise myelin as harmless. Further studies are expected to start shortly to confirm whether that in turn prevents relapses of the disease.
Northwestern University in Chicago, which took part in the research, hailed the study as a "big breakthrough".
Researchers, working with scientists in Switzerland and Germany, took billions of white blood cells from nine patients and processed them to carry tiny fragments of myelin.
The cells were then re-injected, training the immune system to tolerate myelin.
Lead researcher Professor Stephen Miller said results showed the treatment stopped the body turning against itself - without the side effects of some other treatments that suppress the entire immune system, leaving patients vulnerable to infections and cancer.
"Our approach leaves the function of the normal immune system intact. That's the holy grail," he said.
Results published in the journal Science show that reactivity to myelin fell by between 50% and 75%.
Swiss authorities have already approved the next stage of clinical trials to confirm whether the treatment prevents progression of the disease. Experiments on mice show that it does.
"In the phase two trial we want to treat patients as early as possible in the disease before they have paralysis due to myelin damage," said Prof Miller.
"Once the myelin is destroyed, it's hard to repair."
Dr Susan Kohlhass, head of biomedical research at the MS Society, said treatments that prevent progression of the disease are "urgently needed".
"Being able to specifically stop the immune system attacking myelin but still keeping it fully functional poses an exciting potential therapy for people with MS," she said.
"More research is now needed and we eagerly await the results of any future larger clinical trials of this therapy."
Source: Sky News Copyright ©2013 BSkyB (05/06/13)
Working with lab mice models of multiple sclerosis (MS), UC Davis scientists have detected a novel molecular target for the design of drugs that could be safer and more effective than current FDA-approved medications against MS.
The findings of the research study, published online today in the journal EMBO Molecular Medicine could have therapeutic applications for MS as well as cerebral palsy and leukodystrophies, all disorders associated with loss of white matter, which is the brain tissue that carries information between nerve cells in the brain and the spinal cord.
The target, a protein referred to as mitochondrial translocator protein (TSPO), had been previously identified but not linked to MS, an autoimmune disease that strips the protective fatty coating off nerve fibers of the brain and spinal cord. The mitrochronical TSPO is located on the outer surface of mitochondria, cellular structures that supply energy to the cells. Damage to the fatty coating, or myelin, slows the transmission of the nerve signals that enable body movement as well as sensory and cognitive functioning.
The scientists identified mitochondrial TSPO as a potential therapeutic target when mice that had symptoms of MS improved after being treated with the anti-anxiety drug etifoxine, which interacts with mitochondrial TSPO. When etifoxine, a drug clinically available in Europe, was administered to the MS mice before they had clinical signs of disease, the severity of the disease was reduced when compared to the untreated lab animals. When treated at the peak of disease severity, the animals' MS symptoms improved.
"Etifoxine has a novel protective effect against the loss of the sheath that insulates the nerve fibers that transmit the signals from brain cells," said Wenbin Deng, principal investigator of the study and associate professor of biochemistry and molecular medicine at UC Davis.
"Our discovery of etifoxine's effects on an MS animal model suggests that mitochondrial TSPO represents a potential therapeutic target for MS drug development," said Deng.
"Drugs designed to more precisely bind to mitochondrial TSPO may help repair the myelin sheath of MS patients and thereby even help restore the transmission of signals in the central nervous system that enable normal motor, sensory and cognitive functions," he said.
Deng added that better treatments for MS and other demyelinating diseases are needed, especially since current FDA-approved therapies do not repair the damage of immune attacks on the myelin sheath.
The UC Davis research team hopes to further investigate the therapeutic applications of mitochondrial TSPO in drug development for MS and other autoimmune diseases. To identify more efficacious and safer drug candidates, they plan to pursue research grants that will enable them to test a variety of pharmacological compounds that bind to mitochondrial TSPO and other molecular targets in experimental models of MS and other myelin diseases.
The journal paper is entitled, "A TSPO ligand is protective in a mouse model of multiple sclerosis."
Source: News Medical (20/05/13)
Initiation of phase 1 trial of remyelinating antibody in people with multiple sclerosis announced(24/04/13)
Mayo Clinic and Acorda Therapeutics, Inc. announced that the first patient has been enrolled in the first clinical trial of rHIgM22, a remyelinating antibody being studied for the treatment of multiple sclerosis (MS). This is a Phase 1 clinical trial enrolling people with MS to assess the safety and tolerability of rHIgM22. The study also includes several exploratory efficacy measures.
In MS, a person’s own immune system destroys myelin, a substance that insulates nerves and facilitates conduction of nerve impulses that control neurological function such as movement and vision. Progressive damage to myelin causes functional impairment in people with MS. Currently there are no approved therapies that stimulate the repair or regrowth of myelin once it has been damaged.
“This remyelinating antibody, if successful in clinical trials and approved, would be a novel approach to treating people with chronic neurologic deficits from multiple sclerosis or other similar conditions,” said Moses Rodriguez, M.D., a neurologist specializing in MS at the Mayo Clinic, whose team initially identified rHIgM22. “We are excited that this Mayo discovery is now being evaluated in people with MS to determine its therapeutic potential.”
“The current standard of MS care does not address the underlying issue of the loss of myelin that leads to progressive functional impairment in people with MS,” said Anthony Caggiano, M.D., Ph.D., Acorda’s Vice President of Research and Development. “Stimulation of remyelination represents a novel and potentially significant advance in the treatment of people with MS, and one which could be complementary to existing therapies. In preclinical studies, rHIgM22 has shown the ability to stimulate production of new myelin and improve function.”
The primary objective of this double-blind, randomized single ascending dose study is to evaluate the safety and tolerability of rHIgM22 in people with MS. The study also includes several exploratory efficacy measures, including magnetic resonance imaging and standard clinical measures used to assess people with MS, such as walking ability. Participants in the trial will receive either placebo or rHIgM22 administered as a single intravenous dose. If rHIgM22 is well tolerated in study groups receiving a low dose of rHIgM22, subsequent groups will receive single infusions of higher doses. Participants in this study will continue receiving their standard MS treatments.
The remyelinating antibody program is the result of a research collaboration between Acorda and the Mayo Foundation for Medical Education and Research. Acorda licensed worldwide rights to patents and other intellectual property for these antibodies related to nervous system disorders under an exclusive license agreement with the Mayo Clinic in September 2000. Dr. Rodriguez is an employee of Mayo Foundation.
About MS and rHIgM22
Multiple sclerosis (MS) is a chronic, usually progressive disease in which the immune system attacks and degrades the function of nerve fibers in the brain and spinal cord by destroying myelin (a process known as demyelination) and eventually the nerve fibers themselves. Myelin is a fatty layer of membranes that insulates nerves, facilitating the transmission of electrical impulses through nerve pathways that control neurological functions such as movement, bowel/bladder function, vision and sexual function.
The cells that make myelin, called oligodendrocytes, can initially repair myelin, but as MS progresses, there is little spontaneous repair. Currently, there are no therapies that repair or restore myelin in demyelinating diseases such as MS. If myelin is able to be repaired it could restore electrical conduction and may serve to protect the exposed nerve fiber from further damage.
Preclinical studies in animal models and laboratory studies have demonstrated rHIgM22 can protect oligodendrocytes (the myelin producing cells) and stimulate them to repair areas of demyelination. rHIgM22 treatment of these animals also resulted in sustained improvements in motor activity.
Source: Acorda Therapeutics (24/04/13)
Ordinary skin cells have been directly converted into the myelinating cells destroyed in multiple sclerosis, according to two new papers in Nature Biotechnology.
Using a process they call "cellular reprogramming," researchers at Stanford University School of Medicine and Case Western Reserve School of Medicine, in two very similar papers, described how they turned the fibroblasts into what appear to be oligodendrocyte precursor cells, in mice. Oligodendrocytes produce myelin, the fatty insulation necessary to allow nerve signal conduction. It is caused by an autoimmune reaction attacking the oligodendrocytes.
" We propose direct lineage reprogramming as a viable alternative approach for the generation of OPCs for use in disease modeling and regenerative medicine," the Stanford team stated in their paper.
In multiple sclerosis, the destruction of oligodendrocytes and myelin results in symptoms such as loss of balance, problems moving arms and legs, loss of coordination and weakness, according to the National Institues of Health. Other problems include loss of bladder control, impaired vision, depression, and memory loss.
To fix these problems, not only must the autoimmune reaction be brought under control, but the myelin must be repaired. That implies producing new oligodendrocytes. Hence, the OPCs, which researchers think could become effective sources of the olgodendrocytes when transplanted. (Transplantion of fully mature cells doesn't seem to work in such studies; the cells seem to need to complete the last step of maturation in their new enviroment to wire into the nervous system.)
But until very recently, making OPCs has extremely difficult. In February, a team led by University of Rochester scientists created oligodendrocytes from induced pluripotent stem cells, which themselves were derived from fibroblasts. These cells were transplanted into animal models of multiple sclerosis, where they produced myelin.
The University of Rochester team's approach added IPS cells to other sources of oligodendrocytes, including stem cells committed to producing neural lineage-committed stem cells and embryonic stem cells. However, all of these sources require the cells to be taken through intermediate steps to get to the desired cell. By contrast, direct conversion offers a less complicated route, and avoids the troublesome pluripotent stage, in which cells are prone to form tumors.
If the Case Western or Stanford technology turns out to be useful for MS patients, it will help confirm the prediction of Ian Wilmut not long ago that direct conversion would become feasible and ultimately supplant the use of stem cells. The Case Western team spelled out this vision in their paper:
"With further optimization, this approach could provide a source of functional OPCs that will complement, and possibly obviate, the use of pluripotent stem cells and fetal cells in cell-based remyelinating therapies," the Case Western paper stated.
The induced oligodendrocyte precursor cells, or iOPCs, just produce oligodendrocytes, the paper said, while neural stem cells and induced neural stem cells are inefficient in producing them, and they produce other unwanted cells such as neurons and astrocytes.
"We have shown that iOPCs integrate into the CNS and myelinate axons of congenitally dysmyelinated mice in vivo after transplantation," the Case Western paper concluded. "However, for iOPCs to have clinical relevance, future studies will have to extend this reprogramming strategy to human somatic cells and demonstrate extensive CNS myelination and long-term functional benefit to transplant recipients."
Source: U-T San Diego © 1995-2013 The San Diego Union-Tribune, LLC (15/04/13)
Researchers at Boston University School of Medicine (BUSM) led by Carmela Abraham, PhD, professor of biochemistry, along with Cidi Chen, PhD, and other collaborators, report that the protein Klotho plays an important role in the health of myelin, the insulating material allowing for the rapid communication between nerve cells. These findings, which appear online in Journal of Neuroscience, may lead to new therapies for multiple sclerosis (MS) and Alzheimer's disease (AD), in which white matter abnormalities are also common but have been largely ignored.
MS is an inflammatory disease which damages the fatty myelin sheaths around the axons of the brain and spinal cord. This destruction, loss or scarring of the sheaths results in a broad spectrum of symptoms. Disease onset usually occurs in young adults, most commonly women.
In MS the myelin is attacked by the immune system and may not be completely restored by myelin-producing cells (mature oligodendrocytes). The researchers discovered that the addition of Klotho protein to immature oligodendrocytes causes them to mature and manufacture proteins needed for the production of healthy myelin.
"These results taken together indicate that Klotho could become a drug target for multiple sclerosis and other white matter diseases, including AD," explained Abraham.
Abraham and her colleagues have identified, and are working on optimizing, a number of small molecules that could form the basis for the development of therapeutic drugs, which would increase the amount of Klotho protein in the brain.
Since Klotho is not only an age suppressor but also a tumor suppressor, as shown by other research groups, interventions with Klotho-enhancing drugs may solve some of the most treatment-resistant human ailments according to Abraham.
Klotho was named after the Greek Goddess and daughter of Zeus, who spins the thread of life. Abraham's lab was the first to publish (in 2008) that Klotho levels in the brain decrease with age.
Funding for this study was provided by grants from the National Institute of Aging and the Alzheimer's Drug Discovery Foundation.
Source: Eureka Alert Copyright ©2013 by AAAS (31/01/13)
Reduced production of myelin, a type of protective nerve fiber that is lost in diseases like multiple sclerosis, may also play a role in the development of mental illness, according to researchers at the Graduate School of Biomedical Sciences at Mount Sinai School of Medicine. The study is published in the journal Nature Neuroscience.
Myelin is an insulating material that wraps around the axon, the threadlike part of a nerve cell through which the cell sends impulses to other nerve cells. New myelin is produced by nerve cells called oligodendrocytes both during development and in adulthood to repair damage in the brain of people with diseases such as multiple sclerosis (MS).
A new study led by Patrizia Casaccia, MD, PhD, Professor of Neuroscience, Genetics and Genomics; and Neurology at Mount Sinai, determined that depriving mice of social contact reduced myelin production, demonstrating that the formation of new oligodendrocytes is affected by environmental changes. This research provides further support to earlier evidence of abnormal myelin in a wide range of psychiatric disorders, including autism, anxiety, schizophrenia and depression.
"We knew that a lack of social interaction early in life impacted myelination in young animals but were unsure if these changes would persist in adulthood," said Dr. Casaccia, who is also Chief of the Center of Excellence for Myelin Repair at the Friedman Brain Institute at Mount Sinai School of Medicine. "Social isolation of adult mice causes behavioral and structural changes in neurons, but this is the first study to show that it causes myelin dysfunction as well."
Dr. Casaccia's team isolated adult mice to determine whether new myelin formation was compromised. After eight weeks, they found that the isolated mice showed signs of social withdrawal. Subsequent brain tissue analyses indicated that the socially isolated mice had lower-than-normal levels of myelin-forming oligodendrocytes in the prefrontal cortex, but not in other areas of the brain. The prefrontal cortex controls complex emotional and cognitive behaviour.
The researchers also found changes in chromatin, the packing material for DNA. As a result, the DNA from the new oligodendrocytes was unavailable for gene expression.
After observing the reduction in myelin production in socially-isolated mice, Dr. Casaccia's team then re-introduced these mice into a social group. After four weeks, the social withdrawal symptoms and the gene expression changes were reversed.
"Our study demonstrates that oligodendrocytes generate new myelin as a way to respond to environmental stimuli, and that myelin production is significantly reduced in social isolation," said Dr. Casaccia. "Abnormalities occur in people with psychiatric conditions characterized by social withdrawal. Other disorders characterized by myelin loss, such as MS, often are associated with depression. Our research emphasizes the importance of maintaining a socially stimulating environment in these instances."
At Mount Sinai, Dr. Casaccia's laboratory is studying oligodendrocyte formation to identify therapeutic targets for myelin repair. They are screening newly-developed pharmacological compounds in brain cells from rodents and humans for their ability to form new myelin.
Dr. Casaccia is the recipient of the Neuroscience Javits Award by the National Institute of Neurological Disorders and Stroke, a division of the National Institutes of Health, who also funded this research (R37-NS42925-10) along with the National Multiple Sclerosis Society.
Source: Science Codex (29/11/12)
Scientists at the Mainz University Medical Center have discovered another molecule that plays an important role in regulating myelin formation in the central nervous system.
Myelin promotes the conduction of nerve cell impulses by forming a sheath around their projections, the so-called axons, at specific locations - acting like the plastic insulation around a power cord. The research team, led by Dr. Robin White of the Institute of Physiology and Pathophysiology at the University Medical Center of Johannes Gutenberg University Mainz, recently published their findings in the prestigious journal EMBO reports.
Complex organisms have evolved a technique known as saltatory conduction of impulses to enable nerve cells to transmit information over large distances more efficiently. This is possible because the specialized nerve cell axonal projections involved in conducting impulses are coated at specific intervals with myelin, which acts as an insulating layer. In the central nervous system, myelin develops when oligodendrocytes, which are a type of brain cell, repeatedly wrap their cellular processes around the axons of nerve cells forming a compact stack of cell membranes, a so-called myelin sheath. A myelin sheath not only has a high lipid content but also contains two main proteins, the synthesis of which needs to be carefully regulated.
The current study analyzed the synthesis of myelin basic protein (MBP), a substance which is essential for the formation and stabilization of myelin membranes. In common with all proteins, MBP is generated in a two-stage process originating from basic genetic material in the form of DNA. First, DNA is converted to mRNA, which, in turn, serves as a template for the actual synthesis of MBP. During myelin formation, the synthesis of MBP in oligodendrocytes is suppressed until distinct signals from nerve cells initiate myelination at specific "production sites". To date, the mechanisms involved in the suppression of MBP synthesis over relatively long periods of time have not been understood. This is where the current work of the Mainz scientists comes in, as they were able to identify a molecule that is responsible for the suppression of MBP synthesis.
"This molecule, called sncRNA715, binds to MBP mRNA, thus preventing MBP synthesis," explains Dr. Robin White. "Our research findings show that levels of sncRNA715 and MBP inversely correlate during myelin formation and that it is possible to influence the extent of MBP production in oligodendrocytes by artificially modifying levels of sncRNA715. This indicates that the recently discovered molecule is a significant factor in the regulation of MBP synthesis."
Understanding the molecular basis for myelin formation is essential with regard to various neurological illnesses that involve a loss of the protective myelin layer. For example, it is still unclear why oligodendrocytes lose their ability to repair the damage to myelin in the progress of multiple sclerosis (MS). "Interestingly, in collaboration with our Dutch colleagues, we have been able to identify a correlation between levels of sncRNA715 and MBP in the brain tissue of MS patients," Robin White continues. "In contrast with unaffected areas of the brain in which the myelin structure appears normal, there are higher levels of sncRNA715 in affected areas in which myelin formation is impaired. Our findings may help to provide a molecular explanation for myelination failures in illnesses such as multiple sclerosis."
Source: MedPage Today MediLexicon International Ltd © 2004-2012 (26/11/12)
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 neurological 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. Demyelination disrupts the ability of nerve cells to communicate with each other, and produces a range of motor, sensory and cognitive problems in MS and other disorders.
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, Ph.D., 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 MS 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 MS patient brain lesions and in the nervous systems of animals with an MS-like disease. The research team, which included OHSU pediatric neurologist Stephen Back, M.D., and OHSU neuroscientist Steve Matsumoto, Ph.D., found that by blocking hyaluronidase activity, they could promote myelin-forming cell differentiation and remyelination in the mice with the MS-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 MS-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 MS. Many other factors can contribute to the problems associated MS 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.”
Source: Bioscience Technology ©2012 Advantage Business Media (01/11/12)
Protein could undo MS nerve damage(05/10/12)
A protein that helps regenerate the protective covering around nerve cells is a “strong candidate” for drug development for diseases like multiple sclerosis, say researchers.
They have identified previously unrecognized properties of the naturally occuring protein, also finding that it enhances brain cell formation and survival.
The protein, pigment epithelium-derived factor (PEDF), has well-known anti-tumor generating properties. But its role in promoting growth of a type of brain cell and regenerating the protective myelin sheaths around nerve cells had not been known, the researchers say.
“Our investigation found that PEDF plays a key role in accelerating regeneration of the myelin sheath,” says study senior author David Pleasure, professor of neurology and pediatrics, and director of the Institute for Pediatric Regenerative Medicine, a collaborative initiative of the University of California, Davis, School of Medicine and Shriners Hospitals for Children Northern California.
“That makes PEDF a strong drug-therapy candidate, because it appears to encourage the regeneration of a type of brain cell called oligodendocyte and is able to repair the damage caused by demyelinative diseases, including MS.”
Pleasure and his colleagues identified PEDF’s functions on the adult central nervous system under both normal and pathological conditions in mouse-model research.
The study was conducted in male and female wild-type mice that were continuously infused with a PEDF/saline suspension. Control mice received daily infusions of saline alone. The study found that in the PEDF infused mice, the PEDF receptor was expressed in various areas of the brain, including the corpus callosum and subventricular zone, reflecting the extensive effects of PEDF.
“What’s unique about our findings is that we demonstrated that the continuous administration of recombinant PEDF into the normal adult mouse brain enhances production of glial cells in a critical portion of the brain,” says Jiho Sohn, a post-doctoral scholar and lead study author.
“In addition, we noted the maturation of oligodendrocyte progenitors in the bundle of nerve fibers that connect the left and right hemispheres of the brain.” The study also documented that PEDF infusion enhances production of oligodendroglial progenitor cells from endogenous neural stem cells in mice with corpus callosum demyelinative lesions.
Multiple sclerosis is one of several disease conditions brought about by demyelination, or damage to the protective sheath around nerve cells.
Demyelination impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.
Multiple sclerosis is believed to be caused by the body’s immune system attacking the myelin coating on the nerves. There are more than 2.5 million people world-wide with multiple sclerosis, for which there is no cure.
The study is published in The Journal of Neuroscience. Other study authors contributed from Cornell University, UC Davis, University of Tokyo, and Northwestern University.
The study was funded by the National Institutes of Health, National Multiple Sclerosis Society, Shriners Hospitals for Children, and a postdoctoral fellowship grant to Sohn from the California Institute for Regenerative Medicine.
Source: Futurity © 2009-2012 Futurity.org (05/10/12)