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A protein that helps build the brain in infants and children may aid efforts to restore damage from multiple sclerosis (MS) and other neurodegenerative diseases, researchers at Washington University School of Medicine in St. Louis have found.

In a mouse model of MS, researchers found that the protein, CXCR4, is essential for repairing myelin, a protective sheath that covers nerve cell branches. MS and other disorders damage myelin, and this damage is linked to loss of the branches inside the myelin.

"In MS patients, myelin repair occurs inconsistently for reasons that aren't clear," says senior author Robyn Klein, MD, PhD, associate professor of medicine and of neurobiology. "Understanding the nature of that problem is a priority because when myelin isn't repaired, the chances that an MS flare-up will inflict lasting harm seem to increase."

The findings appear online in The Proceedings of the National Academy of Sciences.

Mouse models typically mimic MS symptoms by causing chronic immune cell infiltration in the brain, but, according to Klein, the ongoing immune damage caused by the cells makes it difficult for researchers to focus on what the brain does to repair myelin.

For the study, Klein and first author and postdoctoral fellow Jigisha Patel, PhD, used a non-inflammatory model that involves giving mice food containing cuprizone, a compound that causes the death of cells that form myelin in the central nervous system. After six weeks, these cells, known as oligodendrocytes, are dead, and the corpus callosum, a structure that connects the left and right hemispheres of the brain, has lost its myelin. If cuprizone is then removed from the mouse diet, new cells migrate to the area that restore the myelin by becoming mature oligodendrocytes.

Klein's investigations began with the processes triggered by dying oligodendrocytes while mice are still on the cuprizone diet. The dying cells activate other support cells in the brain, causing them to express inflammatory factors.

Klein showed that levels of a receptor for inflammatory factors, CXCR4, peaked at six weeks. If researchers continued feeding the mice cuprizone for 12 weeks, levels of the inflammatory factor and its receptor dropped significantly. At 12 weeks the mice were also unable to restore myelin, suggesting a potential connection between myelin repair and CXCR4.

"This was a surprise, because the main thing CXCR4 has been known for is its role in forming the brain, not healing the brain," Klein says. "But we did know that injury increases the number of brain cells that make CXCR4, so it wasn't an unreasonable place to look."

Klein showed that the cells destined to become oligodendrocytes and repair myelin damage, known as neural precursor cells, have high levels of the CXCR4. The cells come up to the corpus callosum from an area below the ventricles, a noncellular area filled with cerebrospinal fluid.

When scientists blocked CXCR4 from becoming activated or reduced cells' ability to make it, the mice were unable to restore myelin. Neural precursor cells stayed in the ventricle and grew in number but did not move to the corpus callosum to begin repairs.

"Apparently the neural precursor cells have to stop proliferating before they can migrate, and CXCR4 plays a role in this change," Klein says. "CXCR4 also seems to be essential to the cells' ability to develop into mature oligodendrocytes and form myelin."

Klein plans to see if she can restore myelin repair in genetically engineered mouse models of MS with a genetically altered lentivirus that increases levels of an inflammatory factor that activates CXCR4. She also will work with Washington University colleagues to study the new model with advanced imaging techniques in an attempt to further clarify the relationship between loss of nerve cell branches and myelin damage in MS.

"We do not yet know if this myelin repair pathway is somehow damaged or impaired in MS patients," Klein says. "But I like the idea of turning on something that the brain already knows how to make by itself, allowing it to heal itself with its own molecules."

Patel JR, McCandless EE, Dorsey D, Klein RS. CXCR4 promotes differentiation of oligodendrocytes progenitors and remyelination. Proceedings of the National Academy of Sciences, published online May 31, 2010.

Funding from the National Institutes of Health and the National Institute of Neurological Disorders and Stroke supported this research.

Source: Eureka Alert! (08/06/10)

A National Institutes of Health grant will help University of Central Florida researchers explore new ways to potentially reverse the damage caused by multiple sclerosis and other neurological disorders. 

Stephen Lambert, an associate professor in the College of Medicine and a member of UCF's Hybrid Systems Laboratory, has received $428,000, the first installment of a four-year, $1.9 million project. His team will study the breakdown of myelin, a substance that coats and protects nerves inside the brain and spinal cord, enabling electrical signals to reach distant nerve cells and muscles. 

About 400,000 Americans and about 2.5 million people worldwide suffer from MS, according to the National Multiple Sclerosis Society. The drugs that are available now focus mainly on controlling the inflammatory nature of the diseases to limit the development of neuronal damage. They do not reverse the damage caused by the diseases. 

"The process of myelination is extremely complex. By reproducing these complex phenomena in our laboratories, we can learn more about what causes debilitating diseases that affect so many people around the world," Lambert said. "We hope our research will ultimately lead to new drugs that reverse the damage caused by these diseases and help patients lead longer, healthier lives."

Most of the research will take place in the Hybrid Systems Lab in UCF's NanoScience Technology Center. At the center, a research team led by UCF bioengineer James Hickman showed for the first time last year that specialized myelin coating could be produced in the lab environment without the use of any type of growth serum.

The finding is significant because it allows researchers to more clearly study the causes of breaks in myelin and also the impact of proposed chemical treatments. Both could potentially lead to a greater understanding of the causes of neurological disorders such as MS and diabetes-induced peripheral neuropathy.

Hickman's previous work focused on cells in the peripheral nervous system and the nerves that connect the body's limbs and organs to the brain. The new research will, for the first time, explore the breakdown of myelin in the areas inside the brain and the spinal cord using nanotechnology tools.

"The application of the high-tech tools developed in my lab at the NanoScience Center to this complex problem brings us that much closer to developing new drugs and, at some stage, a cure for diseases such as MS," Hickman said. 

Source: Nanowerk ©2010, Nanowerk (11/05/10)

New findings from an international team of researchers probing the nerve-insulating myelin sheath were bolstered by the work of Boston College biologists, who used x-rays to uncover how mutations affect the structure of myelin, a focal point of research in multiple sclerosis and other neurological disorders.

The findings were central to the group's broader conclusion that a set of protein processes required in the early-stage conversion of glucose into fatty acids are critical to the proper formation and layering of myelin membrane, the researchers report in the Proceedings of the National Academy of Sciences.

Boston College Professor of Biology Daniel Kirschner, Senior Research Associate Hideyo Inouye, graduate student Adrienne Luoma, and undergraduate Michelle Crowther partnered with Dutch, Italian, Swiss and Japanese scientists. The research group looked at the composition of myelin lipids for clues about their role in myelin structure and stability, Kirschner said. Myelin sheaths surround the axons of neurons and are considered critical to the proper functioning of the nervous system.

"Myelin is a stack of membranes providing insulation to the axon and with that insulation comes rapid nerve conduction," said Kirschner. "If myelin becomes defective, the membranous insulator becomes leaky and the nerve doesn't conduct as well. If myelin is totally missing along part of an axon, the nerve conduction is blocked."

Using x-ray diffraction, Kirschner's group captured a view of the dynamic membrane assembly in whole nerve samples taken from mice engineered to mimic myelinic diseases. Compared to other microscopy techniques used in the study of myelinated tissue, x-ray diffraction delivers clearer, cleaner and quicker results about the structural integrity of internodal myelin, Kirschner said.

"We were able to tell that the packing of the membranes was abnormal, which could affect the electrophysical properties of myelin," said Kirschner. "We also saw that the packing of the lipids in the myelin lipid bilayers was more disordered in samples from the transgenic mice used here."

Other types of microscopy introduce chemical modifications to the tissue under study. These agents and the time involved in preparing and analyzing such samples can alter the molecular structure and mask the dynamic interactions of myelin. X-ray diffraction requires no chemical treatments and can be completed in about an hour, Kirschner said.

"The advantages of x-ray diffraction are that we can examine and analyze whole pieces of tissue and give information about the effect of the mutation on the native structure of the myelin as well as on its stability," said Kirschner.

The researchers have been focusing on genetically modified mice for approximately four years as part of research into the role of myelin degeneration in a range of diseases of the central and peripheral nervous systems. Kirschner says his team is also exploring use of the technique in animal models of spinal cord injury and repair.

Source: Medical News Today © 2009 MediLexicon International Ltd (27/11/09)

Scientists have uncovered new evidence suggesting that damage to nerve cells in people with multiple sclerosis accumulates because the body's natural mechanism for repair of the nerve coating called "myelin" stalls out.

The study, published today, July 1, 2009, in the print edition of "Genes & Development," was conducted by scientists at the University of California, San Francisco and University of Cambridge. The research was led by co-senior investigator David Rowitch, MD, PhD, a Howard Hughes Medical Institute investigator at UCSF.

The investigation, conducted in mice and in human tissue, showed that repair of nerve fibers is hampered by biochemical signals that inhibit the development of cells known as oligodendrocytes, which function as repair workers in the brain.

Oligodendrocytes form a protective sheath, known as myelin, that insulates the fibrous cables, or axons, radiating from nerve cells. In multiple sclerosis, the immune system's T cells and B cells attack oligodendrocytes, ultimately damaging the myelin sheath to the point that the electrical signals transmitted by the axons beneath it are disrupted.

Remarkably, the brain generally is able to recruit fresh, immature oligodendrocytes to the myelin sheath to repair the damage, for a time. This explains why, in the most common form of the disease, known as relapsing remitting MS, the symptoms -- which range from tingling and numbness in the limbs to loss of vision and paralysis -- disappear or are greatly reduced, for some times months or years at a time.

Ultimately, however, the repair process falters and the disease progresses. In their study, the team set out to see if they could determine what was slowing down myelin repair. They lesioned a small region of white matter in healthy mice, then monitored the repair process, examining the tissue after five, 10, and 14 days.

To find out which genes were contributing to three key stages in the repair process – the recruitment of oligodendrocyte precursors to the site of injury, the maturation of those cells into functional oligodendrocytes, and the formation of a new myelin sheath -- they measured the activity of 1,040 genes. All of the genes they studied encode transcription factors, which regulate the activity of other genes. Their experiments showed that 50 transcription factors are working during key steps in myelin repair.

The team then honed in on a gene called Tcf4, because its expression was strong in damaged areas where repair attempts were under way.

Tcf4 is involved in a cascade of biochemical events known as the Wnt (pronounced "wint") pathway, whose importance has been well recognized in normal development of many tissues, including the brain. Until now, however, Wnt had not been linked to myelin production or repair.

"This is the first evidence implicating the Wnt pathway in multiple sclerosis," says lead author Stephen P.J. Fancy, PhD, a postdoctoral fellow in the Rowitch lab. "We consider this an exciting development in our efforts to understand why the repair process often fails in the disease."

To glean further evidence about Wnt's role, the researchers hyperactivated the Wnt pathway in the oligodendrocytes of mice, which caused a profound delay in repair. Further analysis suggested that the Wnt pathway activation was creating a roadblock that prolonged oligodendrocyte precursor development.

"While the animals eventually showed repair, it was delayed compared to normal mice," says Fancy. The researchers also tested human tissue for the presence of Tcf4, and found the protein in areas damaged by MS but not in healthy white matter. Further, the researchers examined available data from another study and found that many signaling molecules of the Wnt pathway are overactive in lesions of patients with MS.

"This is an important step that we hope will lead to targeted therapies involving the repair process," says co-senior author Robin Franklin of the University of Cambridge.

Now the team is starting to examine some of the other genes it found to be active in the myelin repair process, and is developing new mouse models to help test potential therapies that might manipulate the Wnt pathway to improve myelin repair. Given the pathway's role in so many different processes, however, Rowitch cautioned that targeting Wnt could cause unintended side effects.

The new work may also have implications for another neurological disease, periventricular leukomalacia, which can lead to cerebral palsy in extremely premature infants, says Rowitch. Recent studies by Rowitch and colleagues show a similar inability of oligodendrocytes to perform their important repair function.

"The researchers have made an encouraging finding that could open a new window into the cause of failed neural repair in multiple sclerosis," says Dr. Patricia O'Looney, Vice President of BioMedical Research at the National Multiple Sclerosis Society. "Understanding such mechanisms should help advance the efforts to find valuable treatments for this debilitating disease."

Source: Eureka Alert! (01/07/09)

A new protein identified as critical to insulating the wiring that connects the brain and body could one day be a treatment target for divergent diseases, from rare ones that lower the pain threshold to cancer, Medical College of Georgia researchers say.

They report this week in Proceedings of the National Academy of Sciences Online Early Edition that in the peripheral nervous system that controls arms and legs, the protein erbin regulates the protein neuregulin 1, stabilizing and interacting with the ErbB2 receptor on Schwann cells so they can make myelin, which insulates the wiring.

Their studies in mice have shown that when erbin is missing or mutated, the insulation is inadequate, slowing communication.

"Erbin is like a tuner to make signaling stronger or weaker," says Dr. Lin Mei, the study's corresponding author and director of MCG's Institute of Molecular Medicine and Genetics.

Without erbin, the myelin production system falls apart. Eventually raw, over-exposed nerves can die.

"Receptors for neuregulin 1 just get degraded and lost," says Dr. Mei, Georgia Research Alliance Eminent Scholar in Neuroscience. "Schwann cells can see neuregulin 1 sitting there but they can't do anything without the receptor."

Impaired myelin formation and maintenance is implicated in a variety of neurological and psychiatric diseases including schizophrenia, multiple sclerosis and Charcot-Marie-Tooth neuropathy, a genetic, progressive disease that weakens muscles.

Cancer is an issue because the ErbB2 receptor also is an oncogene highly expressed in tumors. ErbB2 helps cancer cells grow and spread so finding its role in the receptor's stability and function provides a potential new site for targeted cancer therapy, says Dr. Yanmei Tao says, postdoctoral fellow in neurobiology and the study's first author. In fact, antibodies to ErbB2 already are available to patients with breast and prostate.

Source: Bio-Medicine © 2003-2009 Bio-Medicine. (20/05/09)

UMDNJ researchers have identified a key pathway that could lead to new therapies to repair nerve cells’ protective coating stripped away as a result of autoimmune diseases such as Multiple Sclerosis (MS). An article reporting their findings will appear in the May 13 online edition of the Journal of Neuroscience.

Myelin is fatty material that coats and protects the ends of nerve cells. The loss of myelin and myelin-producing cells impairs the ability of nerves to conduct signals. A severe loss may lead to erosion of nerve tissues and result in permanent damage.

“In people with MS that is relapsing-remitting, the body can replace myelin that has been stripped away,” explained Teresa L. Wood, Ph.D., the study’s lead investigator. “But, after repeated attacks, that process of replacement no longer functions well,” she added.

“Our data demonstrate that a novel cellular pathway, called the mammalian target of rapamycin (mTOR), regulates the generation of new myelin-producing cells (oligodendrocytes) and the production of myelin in immature rodent cells,” Wood said. She is a professor in the Department of Neurology & Neurosciences and the Rena Warshow Chair in Multiple Sclerosis at the UMDNJ-New Jersey Medical School.

More work is needed to determine if the key to reactivate remyelination is to stimulate the pathway or if environmental impediments, such as inflammation, also must be overcome to allow the pathway to function normally. “Now at least we know a target to go after to promote repair,” she said.

The researchers’ work may also lead to new therapies for other disorders where the myelin-producing cells are affected, such as autism, Alzheimer's disease, and perinatal brain injury.

The University of Medicine and Dentistry of New Jersey (UMDNJ) is the nation’s largest free-standing public health sciences university with nearly 5,700 students attending the state's three medical schools, its only dental school, a graduate school of biomedical sciences, a school of health related professions, a school of nursing and its only school of public health on five campuses. Annually, there are more than two million patient visits at UMDNJ facilities and faculty practices at campuses in Newark, New Brunswick/Piscataway, Scotch Plains, Camden and Stratford. UMDNJ operates University Hospital, a Level I Trauma Center in Newark, and University Behavioral HealthCare, a statewide mental health and addiction services network.

Source: Medical Technology (13/05/09)

Scientists studying a mysterious neurological affliction in cats have discovered a surprising ability of the central nervous system to repair itself and restore function.

In a study published March 30, 2009 in the Proceedings of the National Academy of Sciences, a team of researchers from the University of Wisconsin-Madison reports that the restoration in cats of myelin — a fatty insulator of nerve fibers that degrades in a host of human central nervous system disorders, the most common of which is multiple sclerosis — can lead to functional recovery.

"The fundamental point of the study is that it proves unequivocally that extensive remyelination can lead to recovery from a severe neurological disorder," says Ian Duncan, the UW-Madison neuroscientist who led the research. "It indicates the profound ability of the central nervous system to repair itself."

The finding is important because it underscores the validity of strategies to reestablish myelin as a therapy for treating a range of severe neurological diseases associated with the loss or damage of myelin, but where the nerves themselves remain intact.

Myelin is a fatty substance that forms a sheath for nerve fibers, known as axons, and facilitates the conduction of nerve signals. Its loss through disease causes impairment of sensation, movement, cognition and other functions, depending on which nerves are affected.

The new study arose from a mysterious affliction of pregnant cats. A company testing the effects on growth and development in cats using diets that had been irradiated reported that some cats developed severe neurological dysfunction, including movement disorders, vision loss and paralysis. Taken off the diet, the cats recovered slowly, but eventually all lost functions were restored.

"After being on the diet for three to four months, the pregnant cats started to develop progressive neurological disease," says Duncan, a professor of medical sciences at the UW-Madison School of Veterinary Medicine and an authority on demyelinating diseases. "Cats put back on a normal diet recovered. It's a very puzzling demyelinating disease."

The afflicted cats were shown to have severe and widely distributed demyelination of the central nervous system, according to Duncan. And while the neurological symptoms exhibited by the cats are similar to those experienced by humans with demyelination disorders, the malady does not seem to be like any of the known myelin-related diseases of humans.

In cats removed from the diet, recovery was slow, but all of the previously demyelinated axons became remyelinated. The restored myelin sheaths, however, were not as thick as healthy myelin, Duncan notes.

"It's not normal, but from a physiological standpoint, the thin myelin membrane restores function," he says. "It's doing what it is supposed to do."

Knowing that the central nervous system retains the ability to forge new myelin sheaths anywhere the nerves themselves are preserved provides strong support for the idea that if myelin can be restored in diseases such as multiple sclerosis, it may be possible for patients to regain lost or impaired functions: "The key thing is that it absolutely confirms the notion that remyelinating strategies are clinically important," Duncan says.

The exact cause of the neurological affliction in the cats on the experimental diet is unknown, says Duncan, who was not involved in the original study of diet.

"We think it is extremely unlikely that [irradiated food] could become a human health problem," Duncan explains. "We think it is species specific. It's important to note these cats were fed a diet of irradiated food for a period of time."

In addition to Duncan, authors of the new PNAS study include Alexandra Brower of the Wisconsin Veterinary Diagnostic Laboratory; Yoichi Kondo and Ronald Schultz of the UW-Madison School of Veterinary Medicine; and Joseph Curlee, Jr. of Harlan Laboratories in Madison.

Source: Science Daily © 1995-2009 Science Daily LLC (01/04/09)

A delay in traffic may cause a headache, but a delay in the nervous system can cause much more. University of Missouri researchers have uncovered clues identifying which proteins are involved in the development of the nervous system and found that the proteins previously thought to play a significant role, in fact, do not. Understanding how the nervous system develops will give researchers a better understanding of neurological diseases, such as multiple sclerosis and Charcot-Marie-Tooth disorders.

"Speed is the key to the nervous system," said Michael Garcia, investigator in the Christopher S. Bond Life Sciences Center and assistant professor of biological sciences in the MU College of Arts and Science. "The peripheral nervous system 'talks' to muscles through nerve impulses in response to external stimuli. When babies are born, they do not have fully developed nervous systems, and their systems run slower. Eventually, the nervous system matures. Our study tried to understand that maturation process."

The process of nerve cells maturation is called myelination. During myelination, a layer of myelin (electrically insulating material) wraps or forms around the axons (part of the nerve cell that conducts electrical impulses). Nerve impulses travel faster in myelinated nerve cells.

"Myelination is important for signal transmission because it increases nerve conduction velocity," Garcia said. "The relationship between axons and myelinating cells is a reciprocal one, with each cell type sending and receiving signals from the other cell. One signal originates from myelinating cells and results in a large increase in axonal diameter."

When nerve cells are unmyelinated, the axon has a smaller diameter and contains neurofilaments that are less modified and are more compact. Neurofilaments are a group of proteins that are essential for diameter growth. The protein group includes neurofilament subunits that are classified as light, medium and heavy. Loss of all neurofilaments in the axon results in myelinated axons with slowed conduction velocities.

For the last 15 years, the proposed underlying mechanism for an axon's diameter growth has focused on myelin-dependent modification of regions of neurofilaments that are located within the heavy and medium subunits. In a previous study, genetically removing the region of the medium subunit that is modified impaired growth and slowed nerve conduction. However, this did not directly test if the proposed modification was required as a much larger region was genetically removed.

In the current study, researchers genetically altered the neurofilament medium subunit such that it could no longer be modified in response to myelination. Surprisingly, Garcia found that prevention of what was thought to be an extremely important modification did not affect axonal diameter.

"It is now clear that the basic mechanism for how neurofilaments affect axonal diameters remains unanswered," Garcia said. "This discovery introduces a lot of new questions."

Source: e! Science News © 2009 Eureka! Science News (04/02/09)

Anyone with a sweet tooth knows that too much of a good thing can lead to negative consequences. The same can be said about the signals that help maintain nerve cells, as demonstrated in a new study of myelin, a protein key to efficient neuronal transmission.

Normal nerve cells have a myelin sheath, which, much like the insulation on a cable, allows for rapid and efficient signal conduction. However, in several diseases the most well-known being multiple sclerosis demyelination processes cause the breakdown of this "insulation", and lead to deficits in perception, movement, cognition, etc. Thus, in order to help patients of demyelinating disease, researchers are studying the pathways that control myelin formation and maintenance.

A new study by University of California scientists examines the role of a structural protein, called lamin, in maintaining myelin. They found that, while lamin is necessary in the initial stages of myelin formation, too much lamin promotes myelin breakdown. Further investigation led the researchers to the discovery of a signal that fine-tunes lamin expression. This signal, a microRNA called miR-23, can turn down lamin gene expression, and thereby prevent demyelination due to lamin overexpression.

This new work reported in Disease Models & Mechanisms (DMM), dmm.biologists.org, adds another piece to the puzzle that is understanding myelin formation and maintenance. Additionally, the identification of miR-23 as a myelin regulator introduces a new potential drug target in developing treatments for demyelinating illness.

Source: Bio-Medicine © 2003-2008 Bio-Medicine. (02/02/09)

Reversing the damage done by multiple sclerosis would be a dream come true for patients of the debilitating disease, and there is some promising research working toward that goal.

The condition is thought to occur when the body literally attacks itself and current therapies only seek to slow or stop that situation. But Biogen Idec Inc. (BIIB) is developing a drug that may repair the damage to the nervous system from the disease, a prospect that could also aid victims of other neurological conditions.

"This is the first entry into our clinical pipeline, or really in anyone else's pipeline that we are aware of, for a truly restorative therapy for MS," said Ken Rhodes, vice president of discovery neurobiology at Biogen.

Though the Cambridge, Mass., biotech company is hopeful for the drug's development, it is yet to be tested in humans and, assuming success, it wouldn't be available to patients for many years.

Much remains unknown about multiple sclerosis, but it is thought to be an autoimmune disease that occurs when the body attacks myelin, the protective insulation surrounding the nerve fibers called axons in the central nervous system. The myelin damage can distort or block messages carried by the axons and result in a wide variety of symptoms such as vision problems, limb numbness and paralysis.

Though the cause is a mystery, MS is thought to develop from some degree of genetic predisposition working in combination with environmental triggers earlier in the life. It is more common in women and tends to develop between the ages of 20 and 50, according to the National Multiple Sclerosis Society.

Current treatments for the disease all involve trying to alter the immune system's ability to attack the nervous systems, notes John Richert, executive vice president of research and clinical programs for the MS Society.

A popular group of drugs are the beta-interferons, which reduce disease flare ups and are similar to proteins that play a role in the immune system. Those are Biogen's Avonex, Bayer AG's (BAY.XE) Betaseron, and Rebif, marketed by Pfizer Inc. (PFE) and Germany's Merck KGaA (MRK.XE).

Teva Pharmaceuticals Industries Inc. (TEVA) makes Copaxone, which seems to fight the nerve-attacking immune cells by acting as a myelin decoy. Biogen and partner Elan Plc (ELN) also sell Tysabri, which prevents those immune cells leaving the blood stream so that they can't get to the brain or spinal cord.

Early Success

The focus of much of Biogen's current discovery research in MS is focused on restorative therapy, but its most advanced program is led by biologist Sha Mi, who joined the company in 2000 and studied why the axons in MS lesions weren't generating new myelin.

Research found that cells called oligodendrocytes were being prevented from undergoing the needed differentiation for them to build new myelin.

Furthermore, Mi found that the so-called LINGO molecule was inhibiting that differentiation and that using an antibody to block LINGO's function could allow myelin to regenerate.

"When we block LINGO function, we can see robust oligodendrocyte differentiation, and they interact with the axon for remylination," said Mi.

The antibody has been shown to be effective in mouse models that are accepted as being useful for mimicking the properties of MS.

The antibody helped the mice grow new myelin, and it also helped with the integrity of the nerve fibers, in comparison to untreated mice, thus aiding nerve function. More myelin growth occurred closer to the site of the antibody application, also suggesting its responsibility for the effects.

The research showed that the antibody didn't prevent the loss of myelin in an animal model, but it did reduce the effects of disease progression.

Though the development is clearly exciting, the antibody is only in toxicity studies that are expected to be completed later this year. Biogen expects to file an Investigational New Drug application with Food and Drug Administration in the fourth quarter and begin human studies starting shortly thereafter.

Rhodes noted that the next goal is to conduct proof-of-concept studies to determine if the drug inhibits LINGO function in humans with the same positive effects.

Hopeful Future

The possibility of repairing damage done by MS and reducing symptoms of the disease would be revolutionary for MS patients, but Dr. Richert believes that currently used therapies are likely to continue as the best treatment for new patients who may not have a lot of nerve damage.

Regeneration would be used on patients who already have neurological deficits, he said, as well as those whose disease continues to progress regardless of treatment.

In order to provide the best benefit, Dr. Rhodes said that the anti-LINGO antibody would likely be used in combination with one of the more traditional immunosupressive approaches.

"As you dampen the immune response, you treat with anti-LINGO to try and actually facilitate recovery and repair," he said.

If successful, the antibody could have a future in treating other neurological disease such as Parkinson's, or even help repair damage done to the spinal cord.

Biogen has a number of programs to explore the antibody's use in other diseases but is cautious on any of those prospects.

"The preclinical data supporting the utility of those indications isn't as well developed yet as it is with MS," Dr. Rhodes said.

Source: CNN Money.com © 2009 BigCharts.com Inc. (14/01/09)

Scientists find key step in maintaining myelin.

In a new study, researchers at the Montreal Neurological Institute (MNI), McGill University, and the Université de Montréal have discovered an essential mechanism for the maintenance of the normal structure of myelin, the protective covering that insulates and supports nerve cells (neurons). Up until now, very little was known about myelin maintenance.

This new information provides vital insight into diseases such as Multiple Sclerosis (MS) and other progressive demyelinating diseases in which myelin is destroyed, causing irreversible damage and disrupting the nerve cells' ability to transmit messages. The research, published recently in the Journal of Neuroscience, is the first to identify a role for the protein netrin-1, previously characterised only in the developing nervous system, with this critical function in the adult nervous system. This research was funded by the MS Society of Canada and the Canadian Institutes of Health Research.

Netrin-1, a protein deriving its name from the ancient Indian language, Sanskrit, word for 'one who guides,' is known to guide and direct nerve cell axons to their targets. In the molecular biological studies conducted by the team, they found that blocking the function of netrin-1 and one of its receptors in adult neural tissue causes the disruption of myelin.

"We've known for just over 10 years that netrin is essential for normal development of the nervous system, and we also knew that netrin was present in the adult brain, but we didn't know why. It is fascinating that netrin-1 has such a vital role in maintaining the structure of myelin in the adult nervous system," says Dr. Tim Kennedy, a neuroscientist at the MNI and the senior investigator of this study, "continuing to pursue the implications of that are incredibly exciting."

"Our mission is to find a cure as quickly as possible and enhance quality of life," says Karen Lee, assistant vice-president of research programs for the MS Society of Canada. "We are pleased to be involved in funding work that supports our mission and feel that this research takes us closer to understanding the players and processes that could aid in remyelination."

The results of this study, a collaboration between Dr. Kennedy's laboratory, clinician-scientists in the Neuroimmunology group at the MNI headed by Dr. Jack Antel, and Dr. Adriana Di Polo's laboratory at the Université de Montréal, are especially significant in Canada which has one of the highest rates of Multiple Sclerosis (MS) in the world with approximately 1,000 new cases of MS diagnosed each year.

''This is an exciting new area of research that could lead to new treatment strategies and ultimately improve the life of the people who suffer from MS. We are proud to be funding this collaborative research between basic and clinician-scientists," said Dr. Rémi Quirion, Scientific Director of the CIHR Institute of Neurosciences, Mental Health and Addiction.

MS is a disease of the central nervous system in which myelin is destroyed. Understanding the factors involved in maintaining myelin and promoting remyelination, offers new therapeutic targets and avenues for the treatment of MS. As described by Dr. Jack Antel, "Current MS therapies aim to block inflammation. In order to protect and restore myelin it is essential to to understand the molecules involved in these processes. This is the new era of the neurobiology of MS." The team is taking the investigation further by teaming up with the MS clinic and doctors at the MNI, providing access to a huge amount of patient data, and enabling them a broader clinical perspective.

Importantly, this newly discovered mechanism implicates a cascade of protein molecules that have not been known to be involved in myelination. The study was carried out in mice and using in vitro cell cultures. The investigators found that myelin develops normally, but then begins to come apart. Interestingly, in some respects this mirrors what happens in some demyelinating diseases like MS, where myelin forms and may be stable for years, but is then disrupted and begins to fail. Specifically, the new findings show that netrin-1 and its receptor are needed to hold paranodal junctions in place, and thereby maintain the structure of myelin.

The paranodal junction is a highly specialized region of contact where an oligodendrocyte cell attaches itself to the nerve cell's axon. This juncture acts as a molecular fence, which organizes and segregates the distribution of key proteins along the nerve cells axon and plays an imperative role in the proper conduction of electrical signals along the length of the nerve cell. When the function of netrin-1 and its receptor is disrupted, the organization of this adhesive junction comes apart, disrupting the function of nerve cells in the brain and spinal cord.

Source: Eureka Alert! (13/11/08)

A new study highlights the role of a charge-switching enzyme in nervous system deficits characteristic of multiple sclerosis and other related neurological illness.

Multiple sclerosis (MS) is one of several diseases in which myelin – the insulator for electrical signaling in the nervous system – breaks down and causes severe deficits in brain and nerve function. Much like the rubber insulation on an electrical cord, myelin surrounds long projections from the body of a neuron, and allows signals to travel down the cell with speed and efficiency. Patients with MS and other "de-myelinating" diseases therefore suffer deficits in balance, coordination, and movement, as well as sensory disturbances, from the loss of this neuronal insulation.

A major research initiative in treating these diseases is identifying the molecular factors and changes that lead to myelin breakdown.

In a new study published in Disease Models & Mechanisms a team of Canadian researchers report on a new mouse model of disease which will help in understanding how demyelination occurs.

Previous research had identified that an enzyme known as peptidylarginine deiminase 2, or PAD2, is increased in patients with MS, and that PAD2 switches a charge on a protein key to myelin stability. Therefore, Abdiwahab A. Musse and colleagues at the University of Guelph and the Hospital for Sick Children in Ontario created a genetically modified mouse expressing too much of an enzyme known as PAD2. They found that these mice had significant loss of myelin, and also have behavioral deficits, such as abnormal movement, balance, and coordination.

Not only does this work present a new mouse model to study demyleinating disease, but it also stresses the importance of PAD in maintaining myelin integrity. Their work highlights PAD as a potential therapeutic target, as well as a potential marker for early detection of MS and other diseases characterized by a loss of myelin.

Source: EurekaAlert! (06/11/08)

MRF's Accelerated Research Collaboration(TM) (ARC(TM)) model creates a unique partnership between academic researchers, scientific and drug discovery advisors and a centralized management team to define and execute on an integrated research plan that will reduce the time to market for a wide range of patient treatments. Focused exclusively at this time on identifying myelin repair drug targets that will lead to treatments for multiple sclerosis by 2009, MRF provides the business infrastructure for a team of some 30 scientists, working together virtually, from different university laboratories in the U.S. By following best business practices, working on a common research plan, sharing their findings in real time, and piggybacking experiments that might otherwise have taken years to accomplish, the scientists have been able to considerably accelerate their research.

CDD enables scientists to collaborate easily across institutional and disciplinary boundaries and empowers new cooperative research strategies, such as MRF's innovative ARC model. The database features the ability to share data with a spectrum of permissions-either selectively with just a few specific colleagues, openly with the entire scientific community, or not at all. This flexibility encourages data sharing where appropriate while protecting intellectual property, so promising approaches can be patented and commercialized.

The software excels at capturing and organizing fragmented data that would otherwise remain dispersed across multiple laboratories. Foundations can easily set-up and manage collaborations involving multiple research groups located anywhere in the world and spanning multiple scientific disciplines. The central database maintains research continuity as participants change and ensures continued access to the results of sponsored research. CDD manages all the infrastructure and presents data to researchers through an intuitive web interface; contextually-aware hyperlinks steer scientists where they need to go without requiring them to master complex tools.

"By working together with CDD, we can fully exploit the value of the preclinical research data generated by our sponsored researchers and advance promising new therapies for multiple sclerosis more rapidly into clinical trials," said MRF Chief Operating Officer Rusty Bromley. "CDD's software perfectly complements MRF's Accelerated Research Collaboration model which relies on multiple groups located throughout the country, each focusing on different aspects of the overall research challenge. Each group contributes different types of data to the collaboration depending on its distinct scientific specialty. CDD's software integrates these efforts, so a virtual network of academic laboratories can drive toward developing new therapies with a degree of focus historically unavailable in academic laboratories."

In addition to making its existing capabilities available to all MRF researchers, CDD will extend the software's range to include target validation and customize the interface for MRF's researchers. "We are delighted to enter into this partnership with MRF," said CDD Founder and President Barry Bunin. "MRF has pioneered a research paradigm that organizes diverse academic groups into highly-structured collaborations with a sharp focus on outcomes. CDD's software was designed specifically to encourage and support this type of research model, so we believe our database will significantly accelerate MRF's efforts."

MRF and CDD will also work together to help other disease research organizations realize the full potential of collaborative research. "While MRF is specifically focused on speeding myelin repair discoveries that will lead to treatments for multiple sclerosis, we believe that our ARC model has implications for research more broadly," said Bromley. "Part of our mission is to enable others to reap the benefits of the ARC model for preclinical drug discovery R&D. A successful partnership with CDD will offer proof of concept to others seeking collaboration tools for similar research efforts."

Source: Collaborative Drug Discovery, Inc. (28/05/08)

LINGO-1 appears to act as a molecular switch that controls the ability of cells in the CNS to produce myelin, the protective cellular sheath surrounding nerve fibres that assists nerves in conducting electrical impulses. When myelin is damaged by autoimmune diseases such as MS, nerve cells lose their ability to send signals to the body. As this damage progresses, these cells may eventually die, contributing to disability. Although MS therapies can slow the progression of this damage, none are able to repair the lost myelin.

Biogen Idec scientists had previously discovered that LINGO-1 may act to prevent myelin repair after injury. In the study published today, by blocking LINGO-1, scientists were able to promote myelin repair and improve recovery in an animal model of MS. "While preliminary, these findings are encouraging and suggest that the anti-LINGO-1 antibody has the potential to repair some of the damage caused to the CNS. This may be an entirely new approach to treating MS,” said Alfred Sandrock, MD, PhD, Senior Vice President, Neurology Research and Development, Biogen Idec. "The anti-LINGO-1 program is a key part of our research and development efforts in MS. We have a diverse pipeline of therapeutic candidates targeting multiple pathways and patient needs with the goal of offering a portfolio of options for people living with this devastating disease.”

In the study, functional recovery from demyelination was modeled by tracking the disease progression of experimental autoimmune encephalomyelitis (EAE), a widely accepted animal model for studying the clinical and pathological features of MS. The anti-LINGO-1 antibody was administered before disease onset and was found to decrease the severity of EAE across all stages of disease progression, when compared to the control treatment group. In a related study, anti-LINGO-1 antibody treatment resulted in significantly reduced EAE symptoms even when it was administered after disease onset.

The study found that functional recovery, as measured by EAE scores, correlated with improved axonal integrity and axonal remyelination. Physiological improvements in axonal integrity were revealed by magnetic resonance DTI imaging. At the cellular level, the production of new myelin sheaths was revealed by histological staining and electron microscopy. "This is a very exciting early indication that therapies targeted at myelin repair within the CNS can have a dramatic effect on behavioral functional outcome in models of multiple sclerosis, and opens the door for the identification of additional regulators of myelin repair that might be used to enhance functional recovery in patients with MS,” said Robert H. Miller, PhD, Principal Investigator, Myelin Repair Foundation and Director of the Center for Translational Neuroscience, Case Western Reserve University.

Anti-LINGO-1 was discovered by Biogen Idec and is one of several programs in the company’s industry-leading research and development efforts in MS.

In addition to its two marketed products, the company has four programs in clinical development for the treatment of MS.

Source: Biogen Idec (01/10/07)

Experimental studies using models of multiple sclerosis (MS) indicate that rapid and extensive remyelination of inflammatory demyelinated lesions is not only possible, but is the normal situation. The presence of completely remyelinated MS lesions has been noted in numerous studies and routine limited sampling of post mortem MS material suggests that remyelination may be extensive in the early stages but eventually fails. However, visual macroscopic guided sampling tends to be biased towards chronic demyelinated lesions.

Here we have extensively sampled cerebral tissue from two MS cases to investigate the true extent of remyelination. Sections were cut from 185 cerebral tissue blocks and stained with haematoxylin and eosin (H&E), luxol fast blue and cresyl fast violet (LFB/CFV) and anti-myelin oligodendrocyte glycoprotein, human leucocyte antigen-DR (HLA-DR) and 200 kDa neurofilament protein antibodies. Demyelinated areas were identified in 141 blocks, comprising both white matter (WMLs) and/or grey matter lesions.

In total, 168 WMLs were identified, 22% of which were shadow plaques, 73% were partially remyelinated and only 5% were completely demyelinated. The average extent of lesion remyelination for all WMLs investigated was 47%. Increased density of HLA-DR(+) macrophages and microglia at the lesion border correlated significantly with more extensive remyelination.

Results from this study of two patients with long standing disease suggest that remyelination in MS may be more extensive than previously thought.

Source: Neuropathol Appl Neurobiol. 2007 Apr 18

TIGM is a Houston-based nonprofit biotech entity founded in 2005.

The Myelin Repair Foundation, headquartered in Saratoga, Calif., is a nonprofit organisation focused exclusively on studying myelin, the protective insulation surrounding nerve fibres of the central nervous system.

Under the terms of the agreement, TIGM will create up to 15 pairs of custom-designed "knockout mice" -- mice that have specific genes altered for myelin research that scientists are conducting at five different locations over the next year.

The MRF has established an accelerated research collaboration process to bring together leading neuroscientists from universities throughout North America to figure out how myelin is created and damaged and how it can be repaired.

Through this non-traditional collaborative process the MRF hopes to bring treatments for multiple sclerosis and other neurological diseases to the public more quickly.

"By getting knockout mice into the hands of MRF researchers at an accelerated pace, TIGM can support MRF in their race to find breakthrough cures for MS," said Dr. Richard Finnell, TIGM executive director.

"TIGM has unique technology to produce the knockout mice we need far more efficiently than we could do it in our own labs," said Rusty Bromley, MRF's chief operating officer.

Source: Houston Business Journal © 2007 American City Business Journals, Inc