No cure is on the horizon for multiple sclerosis (MS), the pathology of which remains a mystery to researchers. The unpredictable disease, which degrades the insulating myelin of nerves, can strike with varying speeds, to varying degrees of severity, and include any of a host of symptoms, from partial blindness to coordination difficulties to cognitive impairment.
Medication, meanwhile, can have severe side effects and other risks, causing some MS patients to forego treatment altogether.
That is why the VA’s MS Centers of Excellence, which have hubs in Seattle and Portland on the West Coast and Baltimore on the East Coast, spend considerable energy examining the existing medications for how they can best be used, as well as looking for new ways to treat the disease.
“Our research looks at both treatments that are currently available to see what’s most effective and cost-effective, as well as looking in new directions that could provide new therapies that will be beneficial,” explained Walter Royal, MD, associate research director of the MSCoE in Baltimore and an active MS investigator.
Tracking Side Effects
Some drugs approved for treating more advanced or unresponsive MS have been shown to have significant side effects, and physicians must balance that with the benefits they provide to the patient.
Nataliuzab (Tysabri®), an antibody treatment for MS, was temporarily removed from the market in 2005 by FDA when several patients developed progressive multifocal leukencephalopathy (PML) while on the medication. The drug was returned to the market in 2006, but, as required by FDA, VA researchers are keeping a close eye on adverse event reporting.
“Registries have been set up to monitor patients who are on natalizumab looking for complications that can occur from that treatment, the most disturbing of which would be PML. No such cases [have been] identified to date in VA system, but the drug has only relatively recently been introduced into the VA,” Royal said. “So we would not expect the cases to, as yet, appear. Both East and West MSCoEs are collaborating on the monitoring on this and other possible complications.”
The Centers for Excellence also are on alert for potential side effects of treatment with mitoxantrone (Novantrone®), made by Serono Inc. In 2005, the FDA approved revisions to the safety labeling for mitoxantrone injection to warn of the risks of cardiotoxicity and secondary acute myelogenous leukemia (AML) associated with its use. The drug is often used for treating secondary progressive MS—a steadily progressing form of MS lacking in the relapses, remissions, and plateaus that characterize Relapsing Remitting MS (RRMS).
“The majority of patients with MS at the time of diagnosis have RRMS. But within 10 to 15 years, half of those will go on to develop SSMS,” Royal said. According to the National Multiple Sclerosis Society, four injectable medications—Avonex®, Betaseron®, Copaxone®, and Rebif®—are generally seen as first-line treatments, with most MS experts recommending the use of one of these medications as soon as RRMS has been diagnosed. In late 2010, FDA approved Gilenya® (fingolimod) the first oral drug for RRMS.
The National Multiple Sclerosis Society noted that Tysabri® is approved for patients who have not gained sufficient benefit from the injectable medications or had problems with side effects, while Novantrone® is approved for MS patients with worsening RRMS or, as Royal pointed out, the 50 percent who develop SSMS.
VA researchers are also examining the potential roots of MS in an attempt to find ways to stave off the disease.
“MS is a disease that is a result of one’s genetic predisposition with genetic factors interacting with environmental factors,” Royal said. “People in our group have been looking at some of these environmental factors, including vitamin D intake and cigarette smoking.”
An examination of National Health Survey data has shown that individuals who smoke cigarettes as young adults have an increased chance of developing MS later in life. “Since then, studies have been initiated in an animal models to look at potential effects of cigarette smoke in triggering inflammatory responses in the nervous system,” Royal said. “That’s shown to be the case, and we expect that to be a useful model for understanding how cigarette smoke exposure and potentially exposure to other sources of smoke might increase the risk of MS.”
VA researchers are specifically looking at environmental factors, such as industrial and chemical toxins, that veterans may have come into contact with during their military service.
Research into the link between vitamin D is further along. “There have been epidemiologic studies which have demonstrated a link between sunlight exposure and lower risk of MS in veterans,” Royal said. “Studies have been done showing that dietary intake of things such as cod liver oil early in life—things known to contain vitamin D—are also associated with lower risk of developing the disease.”
Biomarkers and Neuroprotection
VA investigators are also performing studies to identify biomarkers of MS. One study is looking at T-cell markers, and early reports show that such a marker could be associated with disability from the disease. That marker could be useful for monitoring treatment responses. Another VA researcher is examining expression of RGC-32—a gene that may be predictive of MS exacerbation and response to treatment.
A number of VA studies also are evaluating approaches to neuroprotection—methods to keep the delicate myelin from being damaged by the disease.
One VA researcher is examining the effects of lithium in providing neuroprotection from MS. Another is using an animal model of stem cell transplantation therapy, where bone marrow stem cells are genetically engineered to express a neurotrophic factor. The cells are then administered to the animal intravenously and are allowed to travel to the nervous system.
“The cells go to the nervous system, and there they can be turned on to increase this neurotrophic factor,” Royal said.
At the end of the day, the biggest unanswered question, and one that Royal admits may not be answered by this generation of scientists, is what actually causes MS. But that will not keep researchers from exploring other questions in order to find answers that improve the health of veterans.
“We want to learn what’s the most frequent factor with development of MS in veterans. It may be different than in other populations,” Royal said. “Another issue, which is very important for veterans, is what factors are associated with the progressive form of the disease and what are the best ways to treat that.”
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