2010 Initiative: Full-Force Thrust for MS Research

In 2005, the aim of the National Multiple Sclerosis(MS) Society Promise 2010 Initiative was toraise $30 million and distribute it to researchteams. "Our goal has been to foster collaborationacross various disciplines," said PatriciaO'Looney, MD, director of biomedical researchprograms at the National MS Society.

After the first year of funding, many of the selected teams are presenting preliminary results. These researchers are focusing on 4 underexplored areas of the disease, O'Looney said.

Investigators working on the MS Lesion Project are examining lesion patterns by analyzing brain tissue samples from biopsies and autopsies. The Sonya Slifka Longitudinal MS Study is examining the effects of the disease on patients' daily lives. In addition, a network of pediatric MS Centers of Excellence have been established to set standards for care, offering medical and psychosocial support to patients younger than 18 years and their families. Those working on the Nervous System Repair and Protection Initiative are noninvasively monitoring tissue repair to determine treatment effectiveness, seeking to move animal studies to human testing.

"We determined that these 4 areas of research are important for our understanding and the treatment of MS," said O'Looney. "They just needed a push in the right direction." The MS Society is currently funding about 400 investigator-initiated programs and has provided over $400 million of support for outstanding research to MS investigators worldwide.

MS LESION PROJECT

The MS Lesion Project was established to help researchers gain an understanding of lesion patterns. "We know that no 2 people with MS are alike. This study is looking at what is causing the damage," said O'Looney. "This study overlaps a bit with [research on] repair, because it reports on concepts related to remyelination."

The initiative is being led by Claudia F. Lucchinetti, MD, professor of neurology at the Mayo Clinic, Rochester, Minnesota. Her collaborators are from the United States, Germany, and Austria. They have amassed a large collection of tissue samples from patients with MS that have been obtained through brain biopsy or autopsy, according to O'Looney.

Lucchinetti and colleagues have been chosen to receive $1.2 million over a 3-year period for funding of the project. They are currently focused on identifying immune cells and immune factors involved in tissue destruction.

A recent autopsy study¹ by Lucchinetti's team showed that an extensive number of patients had remyelinization presenting as shadow plaques. They looked at forebrain tissue samples from 51 patients with MS in which 1026 lesions were analyzed. Disease severity varied, with 5 samples of acute disease, 7 with relapsing-remitting MS, 18 with secondary progressive MS, and 11 with primary progressive MS. Ten had an unknown clinical course.

The researchers found that extensive remyelination was present in a subset of patients with chronic MS. Shadow plaques also were found more frequently in patients with relapsing-remitting and primary progressive disease than in patients with secondary progressive MS. The plaques also were found in those with long-standing chronic disease who died at older ages.

Lucchinetti and her team also are examining characteristics of the patients from whom tissues were taken. Characteristics include clinical symptoms and stages of disease, response to therapy, MRI data, and immunological findings in blood samples, said O'Looney. The researchers hope to correlate the clinical manifestations of the disease and MRI data with the pathology seen directly in brain tissue. The hope is that this research will help clinicians identify which patients will respond best to treatments, said O'Looney.

PEDIATRIC TREATMENT CENTERS OF EXCELLENCE

MS Centers of Excellence were chosen in areas across the United States to offer optimal medical care and psychosocial support to children and adolescents with MS and other related demyelinating conditions, according to Bianca Weinstock-Guttman, MD, associate professor of neurology and director of the Baird MS and Pediatric MS Center at the Jacobs Neurological Institute, State University of New York in Buffalo. "In the past year, the 6 centers of excellence have come together to begin sharing best practices and start research that will result in a better understanding of the early stages of MS and hopefully lead to a cure of the disease," she said.

These centers also offer programs that educate families, health care professionals, and the public about pediatric MS. In addition, researchers from the 6 centers are working together to learn more about the environmental and genetic factors associated with the disease. The centers are staffed by teams of pediatric neurologists and adult MS experts, neuropsychologists, social workers, pediatric nurses, neuro-ophthalmologists, and psychiatrists.

"Our partnership with the National MS Society helps us provide the children and their families with the support and services they need to better understand, manage and cope with the disease," said Weinstock-Guttman. After the first year of funding, most data collected have been from studies from her institution, she said.

Her research team recently presented study findings at the Pediatric Academic Societies' Annual Meeting, which took place May 5 to 8 in Toronto and at the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, which took place September 27 to 30 in Madrid. One study,² presented during a poster session at the Pediatric Academic Societies' Annual Meeting, summarized a retrospective chart review of 26 patients with a history of demyelination and found that children younger than 10 years had consistently higher levels of systemic inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein. Levels in adolescents were more likely to be normal or only slightly elevated. These elevated markers were not shown to be good indicators of risk of recurrent demyelinating events.

Another study,³ presented at the Congress of the European Committee for Treatment and Research in Multiple Sclerosis, reviewed the records of 22 patients who had white matter lesions on MRI that suggested inflammatory and postinfectious changes. The finding was that older children with monophasic disease akin to acute disseminated encephalomyelitis (ADEM) are less likely to have encephalopathy, although younger children with ADEM may present with frank encephalopathy. This was despite the presence of diffuse gray and white matter lesions on MRI. Weinstock-Guttman and colleagues concluded that better imaging tools are required to detect and evaluate the subtle neurocognitive changes in this patient population.

In another study⁴ presented at the European Committee for Treatment and Research in Multiple Sclerosis Congress, it was shown that patients with a family history of autoimmune disorders had a higher risk of demyelination than children without such family histories. The study included a retrospective chart review of 32 children who had a first demyelinating event. Twelve of 15 patients with family histories of autoimmune disorders had recurrent demyelinating episodes. Only 4 patients among those who did not have family histories of autoimmune disorders had recurrent episodes. The researchers concluded that family history of autoimmune disorders might be predictive of poor outcome.

Researchers from the centers recently prepared another abstract that they hope to present at the 36th Annual Meeting of the Child Neurology Society, which will take place in Quebec October 10 to 13, 2007. The abstract describes the clinical presentation and final diagnoses of children presenting to the 6 centers for evaluation of acquired demyelinating disorders.

The 6 MS Centers of Excellence, named in the Table, have developed a common data set for collection of standardized information. "At the moment each center uses its own database with a similar data set, and a common data repository is under development," said Weinstock-Guttman. They also have developed standardized pediatric MS protocols and neurocognitive batteries. "The centers have come together to share critical resources and develop educational material so that each family will get the same access and information," said Weinstock-Guttman.

SONYA SLIFKA LONGITUDINAL MS STUDY

The Sonya Slifka Longitudinal MS Study follows a population of about 2000 patients with MS and looks at demographic and clinical characteristics; patient use and cost of health services; provider and treatment characteristics; and neurological, economic, and psychosocial outcomes.⁵ The study is being led by Sarah Minden, PhD, assistant professor of psychiatry at Harvard Medical School in Boston.

In a recent report on access to health care,⁶ Minden's research team found that most patients with MS had health insurance, a usual source of care, and access to specialty care. Only 3.8% did not have health insurance, which led the group to estimate that 7000 patients with MS in the United States may not be insured.

Although most patients in Minden and colleagues' study were insured, population-based estimates showed that substantial numbers of the insurance plans to which patients belong fail to cover prescription medications, limit patient access to specialists, and restrict patients' choice of hospitals and providers.

It also was observed that 9% of patients in the study did not have a usual source of MS care-a percentage that can be extrapolated to 15,800 total patients with MS in the United States. In addition, 11.8% did not have a usual source of general health care, which would correspond with 17,300 patients with MS; and 31% did not see the specialists that they or their physicians wanted them to see, which would correspond to 57,400 patients nationwide.

A number of patients also had difficulty in getting prescriptions and medical services: 10.5%, which would correspond to 19,400 patients with MS, had difficulty in obtaining prescription medication; 4.1% or 7600 patients encountered obstacles accessing care; and 2.4% or 4500 patients could not obtain mental health services. Out-of-pocket health care costs were found to be twice the amount paid by the general population.

As well as studying treatment patterns, costs, and patient demographics, Minden's team also tracks patients in whom MS has been recently diagnosed. Information from this subset lets health professionals and researchers chart the course of the disease from the very beginning.

REPAIR AND PROTECTION INITIATIVE

The 4 research teams working on the Nervous System Repair and Protection Initiative in the United States and Europe will receive a total of $15.6 million in funding by 2010. O'Looney said these projects will hopefully lead to clinical trials. "Here is an area that the MS Society felt needed to be targeted proactively by the scientific community-to think about repairing areas of the CNS and protecting those areas as well as areas that have not been damaged yet," she said.

Within the first year of research, Peter Calabresi, MD, assistant professor in the Department of Neurology at Johns Hopkins University, and colleagues have discovered how myelin-associated glycoprotein (MAG) communicates with and protects axons, even when MAG is no longer part of the myelin sheath. A new model is being tested to determine the effects of axons passing through areas of injury.

Calabresi's team has discovered that proteins released by T cells not only cause damage to nerve cells but inhibit nerve precursor cells that are trying to repair the brain. A high throughput system to rapidly screen neuroprotective agents in an automated system is also in development.

His team also is exploring new imaging techniques. MRI software using stronger 3-tesla magnets is creating pictures of fiber tract pathways in patients' brains and spinal cords, which may allow the researchers to discriminate axonal from myelinic damage.

The effectiveness of optical coherence tomography (OCT) to measure neurofiber layers in the optic nerve is also being examined. This new OCT testing may allow researchers to easily quantify outcomes in future clinical trials of neuroprotective agents, according to Calabresi. The team is planning a multicenter clinical trial in patients with acute optic neuritis to test whether a new neuroprotective drug can limit axonal loss.

Gavin Giovannoni, MBBCh, PhD, professor of neurology at the Royal London Hospital in the United Kingdom, and collaborators are attempting to create methods to transport repair molecules to sites of injury. "We are now investigating mechanisms of immune tolerance in MS and have started to investigate the role of environmental triggers in driving MS disease activity," reported Giovannoni

His team has developed an animal model of secondary progressive MS, experimental allergic encephalomyelitis, which is charac- terized by a period of relapses and remissions that progress to disability. The results have shown that tremors and spasticity develop in the second phase of disease, gradually leading to less mobility. This progressive phase of the disease lends itself to testing symptomatic therapies targeting spasticity and tremor and neuroprotective and neurorestorative disease-modifying therapies.

Giovannoni reported that several drugs, some of which are currently available as licensed therapies for other diseases, are capable of slowing the progression of disability in the animal model. Two of these drugs, lamotrigine (Lamictal) and tetrahydrocannabinol, are currently being tested for neuroprotective potential in clinical trials in the United Kingdom.

Lamotrigine is being tested in an exploratory study to see if it can prevent or slow the development of the progressive shrinking of the brain, which has been seen in subjects with secondary progressive MS. The second study, which is a large multicenter trial, is investigating whether tetrahydrocannabinol, the psychoactive substance in cannabis, can slow the progressive phase of the disease.

Giovannoni's team is also assessing the effectiveness of several new drugs to modify the disease course. One agent, N-(3,4-dimethoxycinnamoyl) anthranilic acid (3,4-DAA) (Tranilast, Rizaben), which is used to treat allergies, appears to reduce the severity of disease by modifying inflammation.

In addition, the team is working to create novel biological and protein-based therapies and engineered stem cells to deliver growth factors to the brain and spinal cord. These therapies consist of a carrier protein and a cargo protein to promote remyelination and repair.

They are also exploring stem cells using animal models. These stem cells are being engineered to be retained in the CNS to produce large quantities of growth factors at sites of active inflammation.

Finally, the team is currently evaluating a panel of biomarkers to measure biological processes in MS, aid in patient selection for clinical trials, and assess the effectiveness of disease-modifying therapies. The group is developing a panel of assays to quantify inflammation, demyelination, remyelination, and nerve cell and axonal growth.

Ian D. Duncan, PhD, professor of neurology at the University of Wisconsin, Madison, is leading a multidisciplinary team to develop imaging technologies using positron emission tomography and MRI to visualize myelin and nerve fiber damage and to detect repair. The team is using experimental allergic encephalomyelitis models (mouse, rat, and monkey) to explore the anti-inflammatory effects of minocycline and the restorative capabilities of oligodendrocyte progenitors transplanted into or adjacent to the lesion.

The group has quantitated the myelin-axon loss during relapses and remissions, showing a correlation between progressive disability and nerve fiber loss. These findings are now being compared with neuroprotective and transplant therapies. The team also hopes to determine whether transplanted cells can survive inflammation and degeneration when transplanted early in the disease course.

An international team headed by Charles French-Constant, PhD, professor of neurological genetics at the University of Cambridge, United Kingdom, is focusing on restoring myelin by identifying and amplifying natural repair factors in the brain and by attempting transplantation of replacement cells.

His team has identified 5 signaling pathways related to oligodendrocyte precursors that may regulate the ability of the precursors to form mature oligodendrocytes and myelin. Receptor tyrosine phosphatase ζ is the group's first target for the promotion of oligodendrocyte formation. The team is also looking to discover transcription factors for remyelination, and has created a genome scale screen of the repair process that examines more than 1000 transcription factors. They have identified about 25 factors, which will be screened to establish exactly where and when they are expressed during repair.

Human oligodendrocyte precursors form new myelin sheaths when transplanted into the brains of mice, according French-Constant. Mouse neural stem cells injected intravenously reach inflamed areas of the CNS, where they reside for months after transplantation, promoting resolution of inflammation and protection of surviving tissue. Tests also have been developed for myelination using cell cultures of oligodendrocytes and axons.

References:

REFERENCES

1.

Patrikios P, Stadelmann C, Kutzelnigg A, et al. Remyelination is extensive in a subset of multiple sclerosis patients.

Brain.

2006;129:3165-3172.

2.

Yeh EA, Ramanathan M, Weinstock-Guttman B. CRP and ESR elevations are associated with acute exacerbations in younger pediatric patients with recurrent demyelinations. Presented at: the 2007 Pediatric Academic Societies' Annual Meeting, May 5-8, 2007; Toronto.

3.

Yeh EA, Duffner PK, Weinstock-Guttman B. Encephalopathy as an associated manifestation during the first event of CNS inflammatory demyelination in a paediatric population. Presented at: the 22nd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis, September 27-30, 2006; Madrid.

4.

Yeh EA, Weinstock-Guttman B. Familial autoimmune disorders increase the risk for recurrent events in paediatric patients with acquired demyelination. Presented at: the 22nd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis; September 29, 2006; Madrid.

5.

Minden SL, Frankel D, Hadden L, et al. The Sonya Slifka Longitudinal Multiple Sclerosis Study: methods and sample characteristics.

Mult Scler.

2006;12:24-38.

6.

Minden SL, Frankel D, Hadden L, et al. Access to health care for people with multiple sclerosis.

Mult Scler.

2007;13:547-558.