Immune Molecule Decreases Severity Of Multiple Sclerosis-like Disease In Mice

ScienceDaily (Jan. 4, 2009) — A group led by Dr. Cedric Raine at Albert Einstein College of Medicine have explored the expression of an immune molecule (CXCL1) that interacts with myelin-producing cells, finding that CXCL1 decreases the severity of disease in a mouse model of multiple sclerosis (MS).

The autoimmune disease multiple sclerosis (MS) attacks the central nervous system, resulting in demyelination of neurons. Myelin-producing cells in the central nervous system are severely depleted in lesions in patients with MS.

Myelin-producing cells express immune receptors and have been shown to respond to the immune molecule CXCL1, although the role of CXCL1 in MS has not been previously explored. Dr. Raine and colleagues examined the effects of CXCL1 specifically expressed in the nervous system in a mouse model of MS. They observed decreased severity of disease and more prominent remyelination in these mice. CXCL1, therefore, may play a neuroprotective role in CNS autoimmune demyelination.

In future studies, Dr. Raine's group plans to determine how CXCL1 mediates protection in MS. "Exploration of these pathways affords novel therapeutic avenues to enhance the limited remyelination typically seen in MS."

Journal reference:

1. Omari KM, Lutz SE, Santambrogio L, Lira SA, Raine CS. Neuroprotection and remyelination after autoimmune demyelination in mice that inducibly overexpress CXCL1. Am J Pathol, 2009, 174:164-176

Adapted from materials provided by American Journal of Pathology, via EurekAlert!, a service of AAAS.

MLA
American Journal of Pathology (2009, January 4). Immune Molecule Decreases Severity Of Multiple Sclerosis-like Disease In Mice. ScienceDaily. Retrieved January 26, 2009, from http://www.sciencedaily.com­ /releases/2008/12/081230074742.htm

Antibody leads to repair of myelin sheath in lab study of multiple sclerosis and related disorders

Mayo Clinic researchers have found that a human antibody administered in a single low dose in laboratory mouse models can repair myelin, the insulating covering of nerves that when damaged can lead to multiple sclerosis and other disorders of the central nervous system.

The study will be presented on Oct. 9 at the American Neurological Association meeting in Washington, D.C.


“The repair of chronic spinal cord injury is seldom modeled in laboratory studies, but it is an important reality for the treatment of humans. The concept of using natural human antibodies to treat disease of this kind has not yet been tested in humans, but these research findings are very promising,” says Moses Rodriguez, M.D., a Mayo Clinic neurologist and the study’s corresponding author. “The findings could eventually lead to new treatments that could limit permanent disability,” states Arthur Warrington, Ph.D., a Mayo Clinic scientist and study author.

Myelin repair normally occurs spontaneously, but in multiple sclerosis and other disorders of the central nervous system, the myelin repair process occurs very slowly or fails altogether. Researchers are trying to determine how to speed up the myelin healing process, which they hope will eventually lead to new treatments for patients.

The antibody, which was genetically engineered from a single cell, binds to myelin and the surface of cells in the brain and spinal cord, then it triggers the cells to begin the repair process called remyelination. This antibody is the first known reagent designed to induce repair by acting within the central nervous system at the damage sites on cells responsible for myelin synthesis.

The study uses laboratory mouse models of chronic progressive multiple sclerosis in humans. The severity of the disease and also success of the treatment were largely defined by how naturally active the mice were, particularly during the night because mice are nocturnal and are especially active at this time. They received a single dose of the antibody. A minimum of 25 mcg/kg was needed to trigger remyelination, which is equivalent to about 2 mg in the average adult, considered a very low dose. The myelin repair plateaued after five weeks in the mice models.

In addition, when combined with daily methylprednisolone, (an immune modulating steroid) the antibody still promotes remyelination in mouse models. This is an important fact because the first multiple sclerosis patients treated with the antibody will have been treated first with methylprednisolone.

As a naturally occurring protein of the immune system, antibodies do not appear to carry any side effects, nor are they toxic -- even when administered at 4,000 times the minimal effective dose -- though the concept has not yet been tested in humans, the researchers say.

In summary, this antibody:

-- Promotes remyelination with a single dose as low as 25 mcg/kg in mice models

-- The remyelination plateaus at five weeks after a single dose

-- Converts a model of chronic immune mediated demyelination to one that repairs with the speed of a toxin induced model of demyelination

In terms of replicating the findings in humans, the researchers have already produced the antibody through genetic engineering and conducted preliminary toxicology experiments in mice showing that 1,000 times the therapeutic dose is not toxic. The study continues to be explored in animal models and eventually, in clinical trials.

In short, the critical finding is that when combined with methylprednisolone, the antibody still effectively promotes remyelination and does not make the mice worse, Dr. Warrington states.

Source: Mayo Clinic

Preclinical Study Published in Nature Medicine Shows Anti-LINGO-1 Antibody Promotes Remyelination

Sep 30 2007, 1:01 PM EST

News source: Business Wire

Biogen Idec (NASDAQ: BIIB) announced today the publication of findings from a preclinical study reporting that the anti-LINGO-1 antibody can promote spinal cord remyelination and axonal integrity, suggesting a potential role as a treatment for multiple sclerosis (MS) and other demyelinating diseases of the central nervous system (CNS). The results are published in the October issue of Nature Medicine, and confirm previously published data that suggested a role for the anti-LINGO-1 antibody in CNS myelin repair.

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 fibers 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.

About Biogen Idec

Biogen Idec creates new standards of care in therapeutic areas with high unmet medical needs. Founded in 1978, Biogen Idec is a global leader in the discovery, development, manufacturing, and commercialization of innovative therapies. Patients in more than 90 countries benefit from Biogen Idec's significant products that address diseases such as lymphoma, multiple sclerosis, and rheumatoid arthritis. For product labeling, press releases and additional information about the company, please visit www.biogenidec.com.

Safe Harbor/Forward-Looking Statements

This press release contains forward-looking statements regarding anti-LINGO-1 antibody, which is currently in the preclinical stage of drug development. Drug development involves a high degree of risk. Only a small number of research and development programs result in commercialization of a product. Factors which could cause actual results to differ materially from Biogen Idec's current expectations include the risk that the company may not be able to demonstrate the safety and efficacy of anti-LINGO-1 antibody at each stage of the clinical trial process; technical hurdles relating to the manufacture of anti-LINGO-1 antibody may be encountered; the company may not be able to meet applicable regulatory standards or regulatory authorities may fail to approve anti-LINGO-1 antibody; and the company may encounter other unexpected hurdles. For more detailed information on the risks and uncertainties associated with Biogen Idec's drug development and other activities, see the periodic and current reports that the company has filed with the Securities and Exchange Commission. Biogen Idec assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

Scientists Show EGFR Protein’s Role in White Matter Repair

Jul 9 2007, 12:52 PM EST

Scientists at Children’s National Medical Center demonstrated that epidermal growth factor receptor (EGFR) protein and its signaling activity are instrumental in myelination and remyelination. Underdeveloped white matter or white matter injuries are linked to conditions including mental retardation, cerebral palsy, and multiple sclerosis.

The researchers used enhanced EGFR to demonstrate the role that this molecule plays as a catalyst to the natural processes of proliferation and migration of progenitor cells, which are integral to white matter development and repair. Inserting enhanced EGFR protein into mouse models showed enhanced myelination/remyelination. Then, using an EGFR protein with reduced biological activity, the researchers found a decrease in myelination/remyelination.

The study also found that progenitor cells in the peri-ventricular zone of the brain contribute to remyelination of white matter lesions and that these lesions naturally prompt progenitor cells to replicate and migrate to the site of the lesion where they are involved in remyelination and functional repair.

The paper will be published in the August issue of Nature Neuroscience.