An FDA-approved drug for high blood pressure, guanabenz, prevents myelin loss and alleviates clinical symptoms of multiple sclerosis (MS) in animal models, according to a new study at the University of Chicago in Nature Communications. The drug appears to enhance an innate cellular mechanism that protects myelin-producing cells against inflammatory stress.
"Guanabenz appears to enhance the cell's own protective machinery to diminish the loss of myelin, which is the major hallmark of MS," said senior study author Brian Popko, PhD, Jack Miller Professor of Neurological Disorders at the University of Chicago "While there have been many efforts to stimulate re-myelination, this now represents a unique protective approach. You don't have to repair the myelin if you don't lose it in the first place."
Multiple sclerosis is characterized by an abnormal immune response that leads to inflammation in the brain and the destruction of myelin - a fatty sheath that protects and insulates nerve fibers. MS is thought to affect more than 2.3 million people worldwide and has no known cure.
Popko and his colleagues have previously shown that oligodendrocytes, the brain cells which produce myelin, possess an innate mechanism that responds to stressors such as inflammation. It temporarily shuts down almost all normal protein production in the cell and selectively increases the production of protective proteins. When this mechanism is malfunctioning or overloaded - by the chronic inflammation seen in MS, for example - oligodendrocyte death and demyelination is significantly increased.
A recent study found evidence that guanabenz, a drug approved for oral administration for hypertension, enhances this stress response pathway independent of its anti-hypertension actions. To test the suitability of guanabenz as a potential treatment for MS, Popko and his team exposed cultured oligodendrocyte cells to interferon gamma - a molecule that increases inflammation - resulting in greatly increased myelin loss and cell death.
Treating these cells with guanabenz prevented myelin loss and restored cell survival to near normal levels. Oligodendrocytes that were not exposed to interferon gamma were unaffected by guanabenz, suggesting that it enhances only an active stress response pathway.
The team then tested the drug on multiple mouse models of MS. When treated with guanabenz, mice that are genetically engineered to express high amounts of interferon gamma in their brains were protected against oligodendrocyte and myelin loss. Treated mice retained several times more myelination and oligodendrocytes than untreated mice.
To study a chronic model of MS, the researchers immunized mice with a component of myelin, triggering an immune response against myelin similar to MS in humans. Clinical symptoms developed, but guanabenz administered a week after immunization significantly delayed the onset of these symptoms and reduced peak severity. Treatment also prevented around 20 percent of mice from developing symptoms at all.
To study the suitability of guanabenz as a therapeutic after MS symptoms have already appeared and peaked, the researchers used a mouse model in which symptoms relapse and remit - cycling from high severity to low severity to high again over time. They administered guanabenz immediately after symptoms peaked, and found a nearly 50 percent reduction in severity during the next relapse cycle.
"Human MS predominantly follows a relapsing-remitting pattern," said co-author Sharon Way, PhD, a National MS Society Postdoctoral Fellow at the University of Chicago. "Our hope is that this approach would provide protection against future relapses by making them milder and less frequent."
The team confirmed that guanabenz acts by temporarily blocking the reactivation of a protein known as eukaryotic translation initiation factor 2 (eIF2α). When deactivated, eIF2α initiates the stress response pathway. Blocking its reactivation results in a prolonged stress response and provides protection against cell death. The researchers hypothesize that guanabenz stimulates a protective cascade - because fewer oligodendrocytes die, less immune cells are recruited to the brain, which results in a decreased inflammatory response and preservation of myelin levels.
The Myelin Repair Foundation, which funded this work as part of a multi-institutional effort to accelerate research and development of treatments for MS, has entered into a cooperative agreement with the National Institutes of Health to assess guanabenz as a therapeutic candidate in MS clinical studies.
"Guanabenz will probably not be a standalone drug, but we hope that it can be developed for use in combination with other medications," Popko said. "Some current treatments can have severe side effects - for example dangerous infections in the brain. It would be of tremendous benefit for patients to have effective, less-risky therapies.
Source: MedicalXpress © Medical Xpress 2011-2014, Science X network (13/03/15)
The Journal of Neuroscience is reporting that a University at Buffalo researcher has discovered a way to keep remyelination going, using a drug that's already on the market.
According to scientists, there is a brief period after the myelin sheath has been attacked and damaged when it is able to repair itself, but this doesn’t last and the damage deteriorates further as someone with MS ages and their condition progresses.
“We have identified a new drug target that promotes stem cell therapy for myelin-based conditions such as MS,” says lead author Fraser J. Sim, PhD, assistant professor in the Department of Pharmacology and Toxicology in the University at Buffalo School of Medicine and Biomedical Sciences.
The study shows it is possible to boost myelination by targeting human oligodendrocyte progenitor cells with solifenacin, an anti-muscarinic drug that currently is approved and marketed to treat overactive bladder.
“Our hypothesis is that in MS, the oligodendrocyte progenitor cells seem to get stuck,” Sim explains. “When these cells don't mature properly, they don't differentiate into myelinating oligodendrocytes.”
In the new study, the approach Sim and his colleagues took was to first characterise the molecular pathways that govern the differentiation of human oligodendrocyte progenitor cells, and then identify drug candidates that would promote differentiation and myelin production.
They found that when a muscarinic type 3 receptor on human oligodendrocyte progenitor cells was activated, differentiation was completely blocked.
“So we thought, if we had something that blocks instead of activates this receptor, could we boost differentiation?” said Fraser. To do that, the researchers turned to solifenacin, the anti-muscarinic drug for overactive bladder; the bladder muscle contains several muscarinic receptors.
“We were excited about this because solifenacin is an approved drug that's already on the market,” said Sim.
To test whether the drug could boost myelin synthesis, the researchers transplanted human oligodendrocyte progenitor cells into mice that could not make myelin. The result was increased differentiation and myelin synthesis from the transplanted human cells.
However, Sim and his colleagues needed a functional endpoint, a way to know that the myelin being made was being translated into improved behaviour or function.
So Sim teamed up with Richard J. Salvi, PhD, SUNY Distinguished Professor in the Department of Communicative Disorders and Sciences, and director of UB's Center for Hearing and Deafness.
Together, they determined that an auditory brainstem response, which records brain wave activity in response to sounds, would be appropriate.
Sim said that it takes a certain amount of time for a signal to go from the ear to the front of the brain: “So in the readout, you get waves that should have a certain time pattern. When there isn't enough myelin, the signalling slows down. And if you add myelin, you should see the signals speed up.”
The tests showed improvement in the response to auditory signals in animals transplanted with the human oligodendrocyte progenitor cells treated with solifenacin.
“We have identified a way to improve human myelination,” said Sim.
The promising results have prompted Sim and his colleagues to seek funding for a small human trial. The study results are all preclinical and no human testing has been done yet.
The current study was funded by America’s National Multiple Sclerosis Society, the Kalec Multiple Sclerosis Foundation and the Empire State Stem Cell Fund.
In addition to Sim and Salvi, other co-authors are Kavitha Abiraman, Suyog U. Pol, Melanie A. O'Bara, Guang-Di Chen, Zainab Khaku, Jing Wang, David Thorn, Bansi H. Vedia, Exinne C. Ekwegbalu and Jun-Xu Li.
The new study adds to Sim's body of research on stem cells and myelination, which previously determined that a critical phase of remyelination fades with age.
Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (02/03/15)
Semaphorin 4D (SEMA4D) is a viable target for therapy in neuroinflammatory and neurodegenerative diseases like multiple sclerosis (MS), according to findings published in Neurobiology of Disease.
Researchers from Vaccinex, Inc. in Rochester, New York conducted a study of mouse models of experimental autoimmune encephalomyelitis (EAE) – a surrogate for human MS – in order to determine if SEMA4D or any specific novel molecular therapy would make a viable target. The investigators created a monoclonal antibody which binds animal model SEMA4D with high affinity and inhibits the binding between SEMA4D and its receptors. In the process, anti SEMA4D binds in vitro to the recombinant SEMA4D, which prohibited the survival and differentiation of oligodendrocytes precursor cells (OPCs) – important for maintaining the myelin coating on neurons. The EAE rodents demonstrated anti SEMA4D significantly inhibited the development of the neurodegenerative diseases by preserving the BBB integrity and axonal myelination.
A further result the researchers noted was that anti SEMA4D tended to aid the migration of OPC to the site of lesions and improved myelin status after inducing demyelination chemically.
The researchers found that in 3 causes of neuroinflammatory disease, which included the breakdown of the brain blood barrier (BBB), apoptosis of OPCs, and activation of microglia, SEMA4D was effective in blocking the activity. Antibodies were vital to this blocking process, the researchers found.
Vaccinex is currently testing an antibody that blocks human SEMA4D called VX15/2503 in a phase 1 clinical trial. That study is designed to test the safety and tolerability in human patients with MS. The results of this study are expected to be available in early 2015. Vaccinex is a clinical stage biotechnology company which focuses on the discovery and development of human therapeutic monoclonal antibodies to treat cancer and neurodegenerative diseases such as MS and Huntington’s disease.
Source: HCP Live © HCP Live 2015 (14/01/15)
University of Edinburgh scientists are set to work with leading biotechnology company Genzyme, a Sanofi company, to carry out drug discovery research that could reduce neuron damage in the brain.
The collaboration - facilitated by Edinburgh BioQuarter's Business Development team - will focus on identifying therapeutic candidates capable of promoting remyelination and reducing neurodegeneration, mostly in relation to Multiple Sclerosis (MS).
MS is caused by damage to myelin, the protective layer that surrounds nerve fibres. This damage affects the transmission of electrical signals from the brain to the rest of the body and results in symptoms such as problems with muscle movement, balance and vision. Over time MS patients accrue disability, which usually slowly gets worse - this is related to neurodegeneration.
A natural process called 'remyelination' can repair damaged myelin and restore nerve function. In MS, however, remyelination is inefficient.
Scientists from the University of Edinburgh have discovered a physiologically-occurring molecule that prevents the cells needed to help repair damaged myelin from reaching the area of damage, which limits remyelination.
By working with Genzyme, co-investigators Dr Anna Williams, of the MRC Centre for Regenerative Medicine, and Dr Scott Webster hope to identify inhibitors of this molecule (or its receptor) to prevent this block and encourage the cells capable of repairing myelin into the area of damage.
Dr. Williams said: "If successful, this will be a step-change in MS treatment as current treatments are unable to repair the damaged neurons that cause the symptoms of MS.
"Ultimately this could reduce neurodegeneration in MS and the accumulation of disability in patients. This treatment could also be used in other diseases where myelin is damaged, such as spinal cord injury."
Dr. Johanne Kaplan, Vice President of Neuroimmunology Research at Genzyme, stated: "We are very much looking forward to a productive collaboration with Drs. Williams and Webster based on our combined expertise in remyelination and drug discovery and development. Remyelination-promoting therapies remain an unmet need and would be of great benefit to MS patients".
Source: MNT © MediLexicon International Ltd 2004-2015 (09/01/15)
Like conducting an errant orchestra to play together, researchers are guiding processes that go awry in multiple sclerosis to repair themselves.
The conductor walks to the stand and takes his place in front of the orchestra. He raises his baton and, with a dramatic flourish, one hundred individuals come to life. From nowhere, the stillness becomes a beautiful harmony as each member takes their part in a complex symphony.
Consider the workings and structure of the human brain – our most complicated organ – in terms of this orchestra. When it works, it is capable of something more remarkable than the greatest musical compositions in human history, but when it is affected by a condition such as multiple sclerosis (MS), "the brain's tightly orchestrated biological functions become discordant – the conductor begins to fail at their job and several instruments go out of tune," said Professor Robin Franklin, Head of Translational Science at the Wellcome Trust-Medical Research Council (MRC) Cambridge Stem Cell Institute and Director of the MS Society Cambridge Centre for Myelin Repair.
His research team and those led by other Stem Cell Institute researchers Drs Thóra Káradóttir, Mark Kotter and Stefano Pluchino are each looking at a different aspect of this errant orchestra. They hope that their collective knowledge will one day help 're-tune' the brains of MS patients to self-repair.
In its simplest terms, MS is a disease in which the immune system turns on itself, destroying the oligodendrocytes that make a protective sheath called myelin, which encases nerve fibres. This halts the transmission of neural messages, and eventually leads to nerve fibre damage, resulting in a progressive loss of movement, speech and vision for the 100,000 people in the UK who have MS. However, the complexities of treating the disease go beyond simply stopping the destruction of myelin, said Franklin: "The myelin damage causes a build-up of debris, which needs removing, and the environment surrounding the cells needs to be conducive to regenerating the sheath. When we think about repairing the damage, we need to be considering several different biological phenomena at the same time."
Although there are drugs available for modifying the early stages of MS – including alemtuzumab (Lemtrada), developed in Cambridge – there are no treatments that regenerate the damaged tissue. Moreover, although the disease evolves over decades, with periods of remission followed by relapses, there is no treatment once patients have reached the progressive stage (estimated to be about 50% of current patients).
Oligodendrocytes – the master manufacturers of myelin – are formed by a type of stem cell in the brain called oligodendrocyte progenitor cells (OPCs), and are responsible for re-wrapping, or remyelinating, the bare axons with myelin in response to injuries or diseases. But this regenerative ability decreases with age and MS. "As the disease progresses, the need for intervention that galvanises the natural healing process becomes ever more important," explained Franklin. "Working with colleagues at the Harvard Stem Cell Institute, we've shown that the effects of age on remyelination are reversible, which gives us some confidence that we can use the brain's own OPCs for myelin regeneration."
However, to understand how to stimulate the brain's own repair mechanisms first requires an understanding of how the brain detects injury and initiates repair.
Thóra Káradóttir believes that one way the brain 'senses' problems are afoot is through the drop in how fast neural messages are passed across the brain. "The difference in speed between an intact neuron and a damaged one can be like comparing the speed of a cheetah to a tortoise," she said. "I'm eavesdropping on the information superhighway by attaching electrodes to neurons and OPCs." Her findings show that damaged fibres release a molecule called glutamate. "It's their 'cry for help' to OPCs. If it doesn't happen, or if the OPCs don't 'hear', then repair is reduced." She is working with Numedicus, a company that specialises in developing secondary uses for existing drugs, to test drugs that she hopes will be able to amplify this signal and increase the repair process.
Meanwhile, Robin Franklin's team has shown that it's possible to kick-start OPCs, driving the formation of oligodendrocytes and sheath formation, using a drug that targets retinoid X receptor-gamma, a molecule found within OPCs. The results are positive and clinical trials will shortly commence in collaboration with Dr Alasdair Coles from the Department of Clinical Neurosciences and the MRC Centre for Regenerative Medicine at the University of Edinburgh.
What's interesting about the rejuvenation of remyelination is that the treatment primarily affected inflammation in demyelinating lesions, and specifically the recruitment of cells called macrophages. These are the body's 'big eaters' – their role is to search out and gobble up rubbish. "We have identified myelin debris as a potent inhibitor of stem cells. Learning how it is being sensed by stem cells enabled us to overcome this inhibition by using drugs such as ibudilast. A clinical trial to test these effects is currently undergoing preparation," explained Mark Kotter. Franklin and Kotter's work is representative of an interesting turn in MS research within the field. Increasingly, investigators are looking at how the environment around the damage can be improved to help natural remyelination. "It's a curious paradox," said Franklin. "MS is caused by the immune system but components of the immune system are also key to its recovery."
Stefano Pluchino's team, for instance, has shown that injecting brain stem cells into mice with MS works in a surprising way. Instead of making new oligodendrocytes (or other brain cells), the cells seem to work by re-setting the damaging immune response, creating better conditions for the brain's own stem cells to replace or restore what has been damaged. He is now developing more-efficient stem cells and new drugs, including nanomedicines, to foster the healing of the damaged brain.
Given the complex landscape of abnormal activities happening in the MS brain, will combination therapies be the way forward? "Certainly," said Franklin. "Over the next ten years we will see an increased understanding of the fundamental biology in MS, we will identify more targets which may yield effective drugs and we'll have more-refined strategies for running clinical trials. What makes Cambridge rare is the spectrum of skills here – from understanding the fundamental biology of myelin repair through to clinical trials."
Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (03/10/14)
Olfactory Pathology in Central Nervous System Demyelinating Diseases.
DeLuca GC, Joseph A, George J, Yates RL, Hamard M, Hofer M, Esiri MM.
Olfactory dysfunction is common in multiple sclerosis (MS). Olfactory bulb and tract pathology in MS and other demyelinating disease remains unexplored.
A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease (MS; n=17), neuromyelitis optica (NMO); n=3), and acute disseminated encephalomyelitis (ADEM); n=7)) was compared to neuroinflammatory (herpes simplex virus encephalitis (HSE); n=3), neurodegenerative (Alzheimer's disease (AD); n=4), and non-neurologic (n=8) controls.
For each case, olfactory bulbs and/or tracts were stained for myelin, axons, and inflammation. Inferofrontal cortex and hippocampus were stained for myelin in a subset of MS and ADEM cases.
Olfactory bulb/tract demyelination was frequent in all demyelinating diseases (MS 12/17 (70.6%); ADEM 3/7 (42.9%); NMO 2/3 (66.7%)) but was absent in HSE, AD, and non-neurologic controls.
Inflammation was greater in the demyelinating diseases compared to non-neurologic controls.
Olfactory bulb/tract axonal loss was most severe in MS where it correlated significantly with the extent of demyelination (r=0.610, P=0.009) and parenchymal inflammation (r=0.681, P=0.003).
The extent of olfactory bulb/tract demyelination correlated with that found in the subjacent adjacent inferofrontal cortex but not hippocampus.
We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early and be highly inflammatory, and is specific to demyelinating disease.
Source: Brain Pathol. 2014 Sep 17. doi: 10.1111/bpa.12209. [Epub ahead of print] & Pubmed PMID: 25230202 (22/09/14)
Whole-brain measures of myelin water fraction (MWF) -- reflecting the amount of myelin present in brain tissue -- correlated significantly with disease duration and disability levels in multiple sclerosis, supporting a role for MWF in patient management and as an outcome in clinical trials, a researcher said here.
In a cross-sectional study of 141 MS patients and 10 neurologically healthy controls, the "skew" of one of two peaks seen in the distribution of MWF across the brain, including normal-appearing white matter as well in MS-type lesions, was associated with Expanded Disability Status Scale (EDSS) score (P=0.000039) and with the number of years since symptom onset (P=0.012), said Elizabeth Monohan, of Weill Cornell Medical College in New York City.
"To date, our study is the first to demonstrate an approach to modeling white matter myelin water fraction to explore clinical variables that may be driving myelin content," she said at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, held jointly this year with its North American counterpart.
"These observations promote the use of myelin water fraction as a biomarker for myelin," she added, noting that the relationship between MWF on the one hand and EDSS and disease duration on the other suggests that "myelin loss is accumulated during the disease and perhaps contributes to the progressive nature of MS."
Demyelination is the chief pathology in MS and is believed to be the driving force behind the physical disabilities that mark the disease in its later stages. Nerve fibers are sheathed in a protective layer of proteins dominated by myelin; its progressive loss leaves nerve axons vulnerable to various insults such that eventually they break down, leading to loss of nerve function.
However, this process has been impossible to witness or measure directly in human patients. Recently, MWF -- measurable with MRI scans as the amount of water within myelin versus the total amount of water in the tissue scanned -- has emerged as a quantitative marker of myelin that can be assessed noninvasively in living patients.
Up till now, though, its clinical applicability has been uncertain, Monohan explained, because it was unclear whether focusing on MWF in lesioned areas was sufficient and also because the scans took a long time to perform and data analysis was difficult.
She said her group had developed a more practical approach to the scans that cut the image acquisition time to just 10 minutes for the whole brain. Moreover, she and her colleagues determined that scanning the whole brain was the right way to go, because there was no solid evidence to indicate that the clinically relevant demyelination occurs only in lesions.
The whole-brain MWF measurement, Monohan said, provides an "unbiased approach" for studying myelin dynamics.
An important finding in the study was that patients showed a "bimodal" distribution in histograms of MWF values -- a small spike in relatively low values and another larger spike in mid-range values. Monohan said that 94% of the patients showed this type of pattern, compared with just one of the 10 controls.
It was the shape of this spike in low values -- primarily the skew, but also its width -- that was most strongly correlated with EDSS and disease duration, she reported. The shape of the larger mid-value spike was associated with EDSS score but not disease duration.
Monohan said her group is pursuing additional studies to look at a broader patient population, with a wider range of EDSS scores and disease durations. Another goal is to examine MWF in patients undergoing treatment with current MS drugs.
Also, longitudinal studies to track within-patient changes in MWF over time will be necessary to determine how it may correlate with lesion evolution and, importantly, disease progression.
The study was funded by the National Multiple Sclerosis Society and the National Institutes of Health.
Study investigators had relationships with Biogen Idec, Teva, Questcor, Genzyme, EMD Serono, Novartis, and Acorda.
Primary source: ECTRIMS-ACTRIMS
Source reference: Monohan E, et al "Clinical disease burden predicts myelin water fraction in multiple sclerosis" ECTRIMS-ACTRIMS 2014; Abstract YI1.3.
Source: Medpage Today © 2014 MedPage Today, LLC. (12/09/14)
People with multiple sclerosis (MS) lose myelin in the grey matter of their brains and the loss is closely correlated with the severity of the disease, according to a new magnetic resonance imaging (MRI) study. Researchers said the findings could have important applications in clinical trials and treatment monitoring. The study appears online in the journal Radiology.
Loss of myelin, the fatty protective sheath around nerve fibres, is a characteristic of MS, an inflammatory disease of the central nervous system that can lead to a variety of serious neurological symptoms and disability. MS is typically considered a disease of the brain's signal-conducting white matter, where myelin is most abundant, but myelin is also present in smaller amounts in grey matter, the brain's information processing center that is made up primarily of nerve cell bodies. Though the myelin content in grey matter is small, it is still extremely important to proper function, as it enables protection of thin nerve fibers connecting neighbouring areas of the brain cortex, according to Vasily L. Yarnykh, Ph.D., associate professor in the Department of Radiology at University of Washington in Seattle.
"The fact that MS patients lose myelin not only in white but also in grey matter has been proven by earlier post-mortem pathological studies," he said. "However, the clinical significance of the myelin loss, or demyelination, in grey matter has not been established because of the absence of appropriate imaging methods."
To learn more about associations between MS and demyelination in both white and grey matter, Dr. Yarnykh and colleagues used a refined MRI technique that provides information on the content of biological macromolecules - molecules present in tissues and composed of a large number of atoms, such as proteins, lipids and carbohydrates. The new method, known as macromolecular proton fraction (MPF) mapping, has been hampered in the past because of the length of time required for data collection, but improvements now allow much faster generation of whole-brain maps that reflect the macromolecular content in tissues.
"The method utilises a standard MRI scanner and doesn't require any special hardware-only some software modifications," Dr. Yarnykh said. "MPF mapping allows quantitative assessment of microscopic demyelination in brain tissues that look normal on clinical images, and is the only existing method able to evaluate the myelin content in grey matter."
The researchers looked at 30 MS patients, including 18 with relapsing-remitting MS (RRMS), the most common type of MS initially diagnosed, and 12 with the more advanced type of disease known as secondary progressive MS (SPMS). Fourteen healthy control participants were also included in the study. Each participant underwent MRI on a 3-Tesla imager, and the researchers reconstructed 3-D whole-brain MPF maps to look at normal-appearing white matter, grey matter and MS lesions. The researchers further compared the results of their imaging technique with clinical tests characterising neurological dysfunction in MS patients.
The results showed that MPF was significantly lower in both white and grey matter in RRMS patients compared with healthy controls, and was also significantly reduced in both normal-appearing brain tissues and lesions of SPMS patients compared to RRMS patients with the largest relative decrease in grey matter. MPF in brain tissues of MS patients significantly correlated with clinical disability and the strongest associations were found for grey matter.
"The major finding of the study is that the loss of myelin in grey matter caused by MS in its relative amount is comparable to or even larger than that in white matter," said Dr. Yarnykh. "Furthermore, grey matter demyelination is much more advanced in patients with secondary-progressive MS, and it is very strongly related to patients' disability. As such, we believe that information about grey matter myelin damage in MS is of primary clinical relevance."
The improved technique has potentially important applications for MS treatments targeted to protect and restore myelin.
"First, this method may provide an objective measure of the disease progression and treatment success in clinical trials," Dr. Yarnykh said. "And second, assessment of both grey and white matter damage with this method may become an individual patient management tool in the future."
Dr. Yarnykh and colleagues are currently conducting additional research on the new method with the support of the National Multiple Sclerosis Society and the National Institutes of Health.
"This study was done on the participants at a single point in time," he said. "Now we want to compare MS patients with control participants to see how myelin content will evolve over time. We further plan to extend our method to the spinal cord imaging and test whether the combined assessment of demyelination in the brain and spinal cord could better explain disability progression as compared to brain demyelination alone."
Source: News-Medical.Net Copyright 2000-2014 AZoM.com Limited (10/09/14)
Cyclic phosphatidic acid treatment suppress cuprizone-induced demyelination and motor dysfunction in mice.
Yamamoto S, Gotoh M, Kawamura Y, Yamashina K, Yagishita S, Awaji T, Tanaka M, Maruyama K, Murakami-Murofushi K, Yoshikawa K.
Multiple sclerosis is a chronic demyelinating disease of the central nervous system leading to progressive cognitive and motor dysfunction, which is characterised by neuroinflammation, demyelination, astrogliosis, loss of oligodendrocytes, and axonal pathologies.
Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death.
In this study, we investigated the effects of cPA on cuprizone-induced demyelination, which is a model of multiple sclerosis.
Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, astrocyte and microglial activation, and motor dysfunction.
Simultaneous administration of cPA effectively attenuated cuprizone-induced demyelination, glial activation, and motor dysfunction.
These data indicate that cPA may be a useful treatment to reduce the extent of demyelination and the severity of motor dysfunction in multiple sclerosis.
cPA is a potential lead compound in the development of drugs for the treatment of this devastating disease.
Source: Eur J Pharmacol. 2014 Jul 30. pii: S0014-2999(14)00577-9. doi: 10.1016/j.ejphar.2014.07.040. [Epub ahead of print] & Pubmed PMID: 25084219 (12/08/14)
When mice chew through the insulation that protects a house’s wires, an electrician can repair the wires. People with multiple sclerosis, whose immune systems malfunction and attack the insulation of their own neural wires, don’t have that option. Helping them could be a very big deal in MS care.
Swiss drug giant Roche, tapping into an unorthodox business model created by a San Francisco venture group, wants to find treatments to help. Roche and Versant Ventures have created the oddly named Inception 5—we’ll explain the name later—to house a promising new way to look for multiple sclerosis drugs, a high-throughput screen developed at the University of California, San Francisco.
Roche will contribute its vast libraries of compounds to test in the UCSF assay, and a seasoned team of drug discovery scientists in the employ of Versant’s Inception group will also try to design new compounds.
Repairing the neural insulation is called remyelination. Myelin is the substance that makes up the sheaths, and it’s also what the immune system mistakes for a pathogen. The attack leaves holes in the myelin, and like a house with faulty wiring, the patient’s nervous system starts to short-circuit, leading to a wide and unpredictable range of neurological symptoms.
While drug makers have produced improvements with drugs that tamp down the immune system’s attack, nothing is available to reverse the actual myelin damage. (Two monoclonal antibody therapies, one from Biogen Idec, Anti-LINGO-1, and another from Acorda Therapeutics, rHIgM22, are in the clinic.)
The UCSF assay, created by neurology professor Jonah Chan, is an innovative way to get at a thorny problem: It’s really hard to build tests that demonstrate remyelination. Neurons, the cells that need to be remyelinated, are finicky to grow in the lab. Also a problem: oligodendrocytes, the cells that produce myelin, don’t wrap their myelin around the axons of neurons in an easily measurable way. (Axons are the branching arms of neurons that transmit electrical signals.)
There are other reasons, too, but Chan created a work-around: Build tiny silica cones that encourage oligodendrocytes to wrap their myelin cleanly. In other words, he built axons from pure glass. And when those silica cones (which Chan calls “micropillars”) are lined up in a testing plate, their cone shape allows measurement of the myelin thickness as it wraps around. Imagine reading the myelin as if it were the rings in the cross-section of a tree.
“Jonah’s done a great job,” said Jay Tung, chief research officer of the Myelin Repair Foundation in Saratoga, CA, which has worked with Chan in the past. “We are ecstatic about pharma, academics, startups, anyone moving the field forward. This is exactly what we want to see.”
“My view is that the missing link for finding candidate therapies for myelin repair has been the lack of a platform for efficient high-throughput screening of agents,” said Timothy Coetzee, chief research officer at the National Multiple Sclerosis Society in New York. The nonprofit funded much of Chan’s work that went into the micropillars. “The complexities of co-culture systems just don’t lend themselves to HTS. Jonah’s technology fills that critical gap.”
With the screening platform, researchers can test how thousands of drugs spur oligodendrocytes to produce myelin. That’s exactly what Inception 5 plans to do.
The group is part of a Versant initiative to keep its own drug-discovery team in-house at a company called Inception Sciences, led by a group of scientists who, at the Merck-Frosst labs in Montreal, had a string of successes including the painkiller rofecoxib (Vioxx)—later withdrawn from the market for safety concerns—and the asthma drug montekulast (Singulair). One of those scientists, Peppi Prasit, and Versant teamed up to create Amira Pharmaceuticals, which they sold in 2011 for $475 million.
Prasit and Versant managing director Brad Bolzon (right) immediately pivoted to launch Inception Sciences, which describes itself as a “small-molecule pharmaceutical incubator.” It is wholly owned by Versant and has two labs, one in San Diego, another in Vancouver. A third is about to open as well.
Instead of turning Inception Sciences into a sprawling biopharma, Versant uses a few million dollars at a time to fund Inception spin-offs that it partners with outside drug companies. (Hence the Inception 5 name; there are four other spinoffs, with more soon to be announced, according to Bolzon.) With Inception 5, Roche is paying for the research and has the option to buy the company outright once the Inception team files an IND, which is industry shorthand for asking the Food and Drug Administration permission to test a drug in humans.
Chan told Xconomy his work had drawn a lot of industry interest, but meeting the Inception scientists at their San Diego facility last year “hooked him.” Two people in particular, the medicinal chemist Brian Stearns and the biologist Daniel Lorrain, were “very impressive,” said Chan. “They’re so focused on developing products and new drugs. It made perfect sense.”
Chan also liked the idea of a third party like Inception between his work and Roche, which previously had asked him directly to screen their compounds in his lab. “That wasn’t appealing,” he said. “I didn’t want to be a service provider for companies.”
Instead, Chan and his students can get back to basic research and leave the screening work to others. “I’m just a lab rat,” he said. “It’s up to the drug hunters to take the next steps.”
Chan and his fellow UCSF neurology professor Ari Green, also an MD who treats multiple sclerosis patients, are among Inception 5’s founders and have an undisclosed equity stake. (Versant is the main owner, and Inception’s employees also take equity in each spinout.)
Even as the micropillar screen goes over to Inception 5, Green is overseeing a 50-person trial at UCSF with a drug he and Chan found with the screen. Like much of the work surrounding myelin repair, Green is taking a creative tack to measure the drug’s effect. The trial measures the speed at which light shone in a patient’s eye is converted into a signal in the brain. Myelin damage to the optic nerve slows that conversion. Patients whose speed improves during the trial might be experiencing myelin repair.
Data could be ready by the end of the year, but the trial isn’t meant to get a new drug on the market. They’re testing an off-patent, over-the-counter antihistamine, and its drowsy effect on patients rule out its potential as an MS drug. “Fatigue is the number-one issue for MS patients,” said Green. “But if this trial goes well, we’ll pursue funding for a large scale clinical trial, because even if it doesn’t lead to development of a therapeutic, it’ll help advance the field.”
It’s a field full of unknowns. As promising as Chan’s micropillars are, they’re synthetic. They only approximate how myelin would wrap around real axons, and they lack the complicating factor of inflammation in the micro-environment. Tung of the MRF says his group has an “intense focus” to move toward a high-throughput screen without using a synthetic material. Inception 5 will work on next-generation assays, too, says Green.
If Roche pulls the trigger and buys Inception 5, it will take the micropillar screen with it, which doesn’t sit well with Tim Coetzee of the NMSS. “If this platform technology got walled off from rest of the world, I’d be worried,” said Coetzee. “This is about MS, but we’re also starting to see defects in myelin in Alzheimer’s, ALS, and other diseases. It’s not as profound right now as MS, but there are other places this technology could have relevance.”
Source: Xconomy © 2007-2014, Xconomy, Inc (23/06/14)
Two teams of researchers report success in stimulating the repair of nerve-insulating myelin in mouse models of MS. Myelin is a major target of immune attacks in MS, and although these are early results and further work is needed, these findings show some promise for strategies to repair damage and restore function for people with multiple sclerosis.
Background: In MS, myelin, the material that surrounds and protects nerve fibers, is damaged in the brain and spinal cord, and so are the cells that make myelin, called oligodendrocytes. Though the replacement cells that could repair myelin, called oligodendrocyte precursor cells (OPCs), exist in the brain, in MS they cannot adequately repair the damaged myelin.
Stem Cell Study: Lu Chen, PhD, Thomas Lane, PhD (University of California, Irvine) and colleagues report that administering neural precursor cells (nerve stem cells) to mice with MS-like disease reduced inflammation, decreased myelin damage, and increased myelin repair. (Stem Cell Reports, published May 15, 2014)
The team injected the stem cells into the spinal cord of mice with an MS-like disease induced by a virus. Although the stem cells were rejected by the body, and were not detectable within eight days after transplant, they were effective nevertheless in reducing the disease. Improvements in motor abilities of the treated mice were still apparent after six months.
The team noted that improvements went along with an increase in a type of immune cell called “regulatory T cells,” or “Tregs.” To test whether the Tregs contributed to the improvements, they blocked Tregs activity, which reduced the stem cells treatments’ impact.
The team speculates that the stem cells may be stimulating the immune environment in a way that activates mouse OPCs, even though the stem cells themselves do not turn into myelin-making OPCs. They are now investigating this idea further to discover the factors released by the stem cells. Ultimately, this information could contribute to the development of stem cell therapies and even cell-free therapies that stimulate recovery in people with MS.
Stimulating Resident Cells: Jessica Williams, PhD, Robyn S. Klein, MD, PhD, and colleagues (Washington University School of Medicine) report that targeting a signaling receptor (docking site) called “CXCR7” on immature oligodendrocytes in mice enhances myelin repair (Journal of Experimental Medicine, published April 14, 2014).
Dr. Klein’s team focused on a messenger protein (chemokine) that interacts with the immature OPCs. They studied mice that were given a toxin called cuprizone, which mimics myelin damage that occurs in the brain during MS. Once cuprizone is withdrawn, myelin repair occurs. The team found that CXCR7 activity increased during myelin damage, and then reduced with myelin repair. When the team administered an experimental compound that inhibits CXCR7, the numbers of OPCs, as well as mature oligodendrocytes, increased within myelin-damaged areas. Myelin repair was enhanced.
These data suggest that CXCR7 might serve as an important therapeutic target to promote myelin repair. Since these studies were conducted in mice, further research is necessary to ultimately determine whether this approach might be an effective approach for stimulating myelin repair in people with MS.
Conclusion: Achieving success in the Society’s priority area of nervous system repair would provide life-changing advances for people with MS. Read more about this research strategy.
Source: US National MS Society (17/06/14)
Bionure Inc. has announced its drug candidate, BN201, was shown to promote myelination — the cellular process of repairing the protective sheath surrounding nerves that is damaged in people with multiple sclerosis (MS). The pre-clinical study was conducted in a novel cell-culture assay developed by the Myelin Repair Foundation (MRF) and assessed at the Foundation’s Translational Medicine Center under a previously announced collaborative agreement.
Bionure and the Myelin Repair Foundation are working together to evaluate BN201 as a potential myelin repair candidate for treating acute optic neuritis and the severe MS relapses that occur in some patients. Acute optic neuritis is a severe inflammation of the optic nerve that may lead to blindness in people with MS. Using the Foundation’s co-culture assay, the collaboration’s scientists were able to show BN201 promotes myelination in animal cells.
“We are working closely with scientists at the Myelin Repair Foundation’s Translational Medicine Center to advance the commercialization of BN201,” said Albert G. Zamora, CEO at Bionure, Inc. “The MRF’s myelin repair assay provided the confidence and independent validation to help us propel BN201 into clinical trials to determine its efficacy in humans. As a result, Bionure will now expand upon the intellectual property that we have for this compound.”
“We are delighted to collaborate with Bionure to advance a potential myelin repair therapeutic for MS and optic neuritis towards commercialization,” said Jay Tung, Ph.D., chief research officer at the Myelin Repair Foundation. “Our collaboration with Bionure exemplifies the value that our Translational Medicine Center brings to industry partners. Our goal is to leverage our non-profit status to partner with industry and accelerate the drug development of potential MS therapeutics that promote myelin repair.”
Source: MarketWatch Copyright © 2014 MarketWatch, Inc (27/05/14)
Real hope for modifying the disease course of multiple sclerosis (MS) may come from strategies to remyelinate damaged neurons and brain cells, says Catherine Lubetzki, MD, of the Pierre and Marie Curie University and Pitie-Salpetriere Hospital in Paris, France. Speaking on April 30, 2014, at the American Academy of Neurology’s 2014 annual conference in Philadelphia, PA, Lubetzki mapped out the pathway her lab is building from basic science to drug development for new MS agents.
She told the audience that treatments effectively targeting the inflammatory component of MS are still lacking. Pilot and phase 2 studies are underway with agents aimed at reducing inflammation, enhancing neuroprotection, and encouraging remyelination; however, the remyelination pathway in particular has not been well understood. Currently, the SPRINT-MS study for ibudilast in relapsing-remitting and primary progressive MS is underway with 250 patients planned to enroll. The phase 2 MS-SMART study of secondary progressive MS will enroll 440 patients in one of four treatment arms to receive riluzole, amiloride, ibudilast, or placebo.
Even given the current and emergent treatment landscape, remyelination, when it does occur, is insufficient to overcome chronic axonal damage and resultant disease progression. To understand why remyelination fails, the processes involved in oligodendrocyte precursor cell (OPC) activity must be made clear. These cells, which migrate to areas of plaque, mature, and eventually wrap around axons to remyelinate, do so through a four-step process. First, the cells are activated; then, they are recruited to migrate. Next, they achieve maturation before finally completing their wrap and myelination of the axon.
Lubetzki’s lab has used a mouse model to examine the transition from quiescent to activated OPCs, and to achieve a better understanding of the transcription profile of mature OPCs. Her group’s work shows that demyelination-induced activation of adult OPCs makes the cells revert to a less mature gene cell, providing cues to promote OPC motility, necessary for activation and recruitment of these cells to the demyelinated areas with plaque burden.
OPCs must then receive guidance for targeted migration to demyelinated areas. Two genes have been identified which seem to have opposing effects on OPC recruitment and remyelination rates. Overexpression of the Sema 3F gene has been associated with increased OPC recruitment and with increased remyelination rates, while overexpression of netrin has the opposite effect, decreasing OPC recruitment and reducing the rate of remyelination. Thus, a primary focus is to target Sema 3F at the lesion site, increasing the rate of remyelination by increased (and targeted) OPC recruitment. Critically, this must be accomplished early in the disease process, when axonal damage may still be reversible.
Lingo-1 has also been identified as a down-regulator of OPC activation and recruitment; researchers are also attempting to achieve early remyelination through use of an anti Lingo-1 monoclonal antibody. Two trials are currently underway examining this drug. The SYNERGY trial plans to follow 400 patients with relapsing-remitting MS over 18 months, while the RENEW trial for sufferers of optic neuritis (another inflammatory demyelinating disorder) will examine the drug’s effects on 80 patients over six months.
Fielding questions from the overflow crowd following the presentation, Lubetzski discussed the outcome measures under consideration to measure efficacy of these drugs in humans. In addition to using magnetic resonance imaging to show remyelination and to follow brain atrophy, positron emission tomography using a myelin ligand may become clinically useful. However, she also emphasized the primacy of maintaining a patient-centered focus, and the critical importance of paying attention to improvement in clinical endpoints.
Source: HCP Live Copyright HCPLive 2006-2014 (02/05/14)
Targeting CXCR7/ACKR3 as a therapeutic strategy to promote remyelination in the adult central nervous system
Current treatment modalities for the neurodegenerative disease multiple sclerosis (MS) use disease-modifying immunosuppressive compounds but do not promote repair. Although several potential targets that may induce myelin production have been identified, there has yet to be an approved therapy that promotes remyelination in the damaged central nervous system (CNS).
Remyelination of damaged axons requires the generation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs). Although OPCs are detected in MS lesions, repair of myelin is limited, contributing to progressive clinical deterioration.
In the CNS, the chemokine CXCL12 promotes remyelination via CXCR4 activation on OPCs, resulting in their differentiation into myelinating oligodendrocytes. Although the CXCL12 scavenging receptor CXCR7/ACKR3 (CXCR7) is also expressed by OPCs, its role in myelin repair in the adult CNS is unknown. We show that during cuprizone-induced demyelination, in vivo CXCR7 antagonism augmented OPC proliferation, leading to increased numbers of mature oligodendrocytes within demyelinated lesions.
CXCR7-mediated effects on remyelination required CXCR4 activation, as assessed via both phospho-S339-CXCR4-specific antibodies and administration of CXCR4 antagonists.
These findings identify a role for CXCR7 in OPC maturation during remyelination and are the first to use a small molecule to therapeutically enhance myelin repair in the demyelinated adult CNS.
Williams JL, Patel JR, Daniels BP, Klein RS.
Sources: J Exp Med. 2014 Apr 14 & Pubmed PMID: 24733828 (29/04/13)
Harvard neuroscientists have made a discovery that turns 160 years of neuroanatomy on its head.
Myelin, the electrical insulating material long known to be essential for the fast transmission of impulses along the axons of nerve cells, is not as ubiquitous as thought, according to a new work lead by Professor Paola Arlotta of the Harvard Stem Cell Institute (HSCI) and the University's Department of Stem Cell and Regenerative Biology, in collaboration with Professor Jeff Lichtman, of Harvard's Department of Molecular and Cellular Biology.
"Myelin is a relatively recent invention during evolution," says Arlotta. "It's thought that myelin allowed the brain to communicate really fast to the far reaches of the body, and that it has endowed the brain with the capacity to compute higher level functions." In fact, loss of myelin is a feature of a number of devastating diseases, including multiple sclerosis and schizophrenia.
But the new research shows that despite myelin essential roles in the brain, "some of the most evolved, most complex neurons of the nervous system have less myelin than older, more ancestral ones" Arlotta, co-director of the HSCI neuroscience program, says.
What this means, Arlotta says, is that the higher in the cerebral cortex one looks - the closer to the top of the brain, which is its most evolved region - the less myelin one finds. Not only that, but "neurons in this part of the brain display a brand new way of positioning myelin along their axons that has not been previously seen. They have 'intermittent myelin' with long axon tracts that lack myelin interspersed among myelin-rich segments.
Arlotta continues: "contrary to the common assumptions that neurons use a universal profile of myelin distribution on their axons, the work indicate that different neurons choose to myelinate their axons differently. In classic neurobiology textbooks myelin is represented on axons as a sequence of myelinated segments separated by very short nodes that lack myelin. This distribution of myelin was tacitly assumed to be always the same, on every neuron, from the beginning to the end of the axon. This new work finds this not to be the case."
The results of the research by Arlotta and post doctoral fellow Giulio Srubek Tomassy, the first author on the report, are published in the latest edition of Science, the journal of the American Association for the Advancement of Science.
The paper is accompanied by a "Perspective" by R. Douglas Fields, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, at the National Institutes of Health, who says that Arlotta and Tomassy's findings raise important questions about the purpose of myelin, "are likely to spark new concepts about how information is transmitted and integrated in the brain."
Arlotta and Tomassy collaborated closely on the new work with postdoctoral fellow Daniel Berger of the Lichtman group, which generated one of the two massive electron microscopy data bases that made the work possible.
"The fact that it is the most evolved neurons, the ones that have expanded dramatically in humans, suggests that what we're seeing might be the "future". As neuronal diversity increases and the brain needs to process more and more complex information, neurons change the way they use myelin to "achieve" more", says Arlotta.
It is possible, said Tomassy, that these profiles of myelination "may be giving neurons an opportunity to branch out and 'talk' to neighboring neurons". For example, because axons cannot make synaptic contacts when they are myelinated, a possibility is that these long myelin gaps may be needed to increase neuronal communication and synchronize responses across different neurons. Perhaps, he and Arlotta postulate, the intermittent myelin is intended to fine-tune the electrical impulses traveling along the axons, in order to allow the emergence of highly complex neuronal behaviors.
Source: News-Medical.Net (22/04/14)
For a healthy nervous system, axons—the long projections of our nerve cells that run throughout our bodies—must be properly insulated.
Much like conventional power cords need electrical insulators around the conducting wires for efficient and effective transfer of current, axons rely on multiple bilayers of myelin to maintain a rapid and optimal transfer of impulses between, for instance, brain and organ, or spinal cord and muscle. These bilayers are composed of lipids (fat molecules), protein, and water.
“Basically, myelin is this multiple stacking of lipid bilayers,” says Dong-Woog Lee, a researcher in the chemical engineering department at the University of California, Santa Barbara. “They need to be compact, and with very little water between the bilayers.”
Lee and colleagues found that even the slightest change in the composition of these myelin bilayers affect their ability to insulate axons. Their findings could offer insights into demyelinating diseases, such as multiple sclerosis.
Stick Like Glue
To observe and measure the characteristics and differences between healthy and diseased myelin bilayers, they studied the ability of these layers to adhere to each other.
The researchers used a highly sensitive instrument, called the surface forces apparatus, that can measure interactions between membranes. The deposited a lipid bilayer on a mica substrate on each of the two opposing surfaces of the apparatus.
Then they immersed the setup in a buffer solution containing myelin basic protein (MBP), a biomolecule commonly found in myelin that gives them adhesive properties and plays a role in maintaining the optimal structure of the myelin sheath.
They brought the two bilayers close together, allowing them to stick to each other, and then pulled them apart, measuring the strength of the adhesion brought about by the MBP “glue” between the bilayers, and also the MBP’s adsorption—the ability of the MBP molecules to stick to the bilayers’ surfaces.
They performed this experiment with both healthy myelin and with “disease-like” myelin bilayers.
“A lipid bilayer simulating a normal or healthy myelin membrane adsorbs this protein much better than a lipid bilayer simulating a multiple sclerosis-type of myelin membrane,” says UC Santa Barbara researcher Kai Kristiansen, “meaning that the protein attaches more strongly to the lipid bilayer and can make two apposing lipid bilayers adhere more firmly to each other and at a smaller distance—which is highly desirable for a well functioning myelin around a neuron.”
Swelling and Multiple Sclerosis
One common characteristic of diseased myelin is swelling, due to various causes such as the autoimmune responses associated with multiple sclerosis and its variants, or in cases of infection or exposure to certain chemicals. Genetics also play a role in the health of myelin.
“When the disease progresses, people can see that they swell and eventually vesiculate, creating scars,” says Lee, who is lead author of the study published in the Proceedings of the National Academy of the Sciences.
The MBP layer between the lipid bilayers also swells with water that seeps in between the double lipid layers. Instead of being a compact, molecule-thick film, the MBP layer becomes more gel-like.
“And since there’s more water between the bilayers, their insulation property decreases,” says Lee. From there, impulses slow down along the axon, or dissipate before they reach their destinations, causing paralysis and loss of function.
Disease–related changes in the lipid domain structures’ size and distribution also causes irregular adsorption of MBP onto the lipid bilayers and weakens their adhesion properties. This in turn also leads to lower nerve insulation.
The next step, according to Jacob Israelachvili, professor of chemical engineering and of materials, is to develop a user-friendly bench-top instrument that could be used in hospitals and clinics to visualize the membranes of certain cells, both healthy and pathological, whose domain structure can be an indicator of the progression of a disease.
“We are currently planning a collaboration with a local hospital to provide us with such membranes, for example, from leukemic blood cells, that we would tag with a suitable fluorescent dye to enable this imaging,” he says.
Source: Futurity © 2014 Futurity (06/03/14)