Winter 2004 Volume 16, Number 2	Hopkins' New MS Center Gives Trials the Thumbs-Up Years of solid science and a boost from technology translate into optimism.
	The new Johns Hopkins Multiple Sclerosis Center has opened with an offering of clinical trials unlike any so far in the institution's history. "With nine neurologists and staff, we can tailor current therapies to patients," says Peter Calabresi, M.D., who heads the center. "But, now, we've begun conducting large international trials (see box) that follow from laboratory discoveries. "Soon," he says, "we'll start smaller translational ones even closer to the edge."
Hopkins' approach to MS to date has clearly advanced what's known of the disease. "Real" MS has been winnowed out from look-alikes, for example. Scientists have described the immune basis of the disease and eliminated trendy but wrong ideas of its cause, saving wasted years of research. "We have been leery of clinical trials, however," says neurology professor Richard Johnson, M.D. "Until recently, they'd have been a lot of work for little benefit." But now a host of high-tech approaches is enhancing the earlier finds, pinpointing targets worthy of trials. Calabresi, new to Hopkins, has worked a decade to show, for example, how white blood cells-memory T cells-primed for autoimmune attack slip from blood vessels into the nervous system. He's hunted characteristic proteins on the surface of those cells drawn "in full battle gear" from MS patients. His study has revealed a protein key to T cell migration and promoted a therapeutic antibody against it. Calabresi's face brightens: "The data in a Phase II trial of 220 patients were stunning! After a once-a-month IV of the antibody, patients had a 90 percent reduction in active lesions and essentially no side effects!" Calabresi's team has also found that chronically "aroused" autoimmune cells-as are found in MS-are peppered with potassium channels. The group is testing specific channel blockers akin to the beta blockers that cardiologists use to counter them. So far, such blockers have quelled symptoms in an animal model of MS. In another lab, neurologist Avindra Nath, M.D., aims to explain how overactive white cells damage neurons. His are key studies of the gradual decline that affects MS patients, one that likely stems from steady deterioration of nerve cells. With Calabresi and Katherine Conant, M.D., as partners, Nath has set up cultures of both activated immune cells from mice and human neurons to track nerve cell decline. Recently, his group substituted MS patients' T cells for the mouse cells. "We aim, of course, to follow the process," says Nath, "and then block it." Once Nath shows how nerve cells go awry, he hopes to use the insights to evaluate the neuroprotective approach-an increasingly earlier defense of patients' nervous systems. "Just controlling inflammation, as most current therapies do, probably isn't enough in the long run." Sanjay Keswani, M.D., is eyeing a possible all-purpose nerve protectant. Clinicians know erythropoietin (EPO) as a hormone that increases the body's supply of red blood cells. But a few years ago, says Keswani, neuroscientists found EPO receptors on nerve cells. "The current idea," he says, "is that a neuron's neighboring glial cells release EPO in times of injury. Now there's enough evidence to try it as therapy." He's planning a pilot study of EPO- already government approved for symptoms of cancer-in patients with an MS-similar disorder. "Still, don't underestimate the value of plain old anatomy," says Johnson. "Recently, we've taken a second look at acute lesions in MS and-surprise-the lesions seem to have different characteristics. Some lack glial cells, some have many. Some have myelin degenerating one way, others, another. The type holds consistent for each patient." Johnson, a world expert on infectious demyelinating diseases, predicts a sharp improvement in MS therapy as it becomes tailored to patients' subtypes. For example, neurologist Douglas Kerr, M.D., is following an aggressive, fatal form of MS. "Signs are that immune activity has run amok," he says. He's starting a clinical trial he probably wouldn't try with a more benign form of MS-a dramatic "rebooting" of the immune system that's given major relief in lupus and myasthenia gravis. The drug, Cytoxan, destroys immune cells but spares the bone marrow stem cells that create them. "The new white blood cells that form, we assume, will have lost their bad autoimmune habits." For picking out less distinct MS subtypes, Nath has turned to proteomics, the science that takes snapshots of a cell's proteins. Analyzing MS patients' spinal fluid with a new type of mass spectrometry that pulls out all the stops, he's already found three unique proteins that rise and fall with MS attacks. Nath's highly protein-literate team from various Hopkins departments helps make sense of the finds. Ultimately, he says, the protein profiles will speed prognosis and help monitor therapy. "We're on the brink of major results-where oncology was in the 1960s, just before you could cure many and put more in remission," says Calabresi. "We should be there soon." Neurologists David Irani, Justin McArthur and Carlos Pardo round off the Center Staff.
Just Say Trials R Us "The time is ripe to try combination trials," says Peter Calabresi, who heads Hopkins' new MS center. His pilot combination of the anti-inflammatory drug beta-interferon and the rheumatoid arthritis medication metho-trexate showed promise. It's led to the present two-year, multicenter trial enrolling 900 patients. That trial now includes the steroid methylprednisolone. Also ready for subjects is a trial of Lipitor, the cholesterol-lowering drug with anti-inflammatory effects. Lipitor is FDA-approved and has few side effects. More important, animal models of MS clearly improved on the drug. The trial targets patients newly diagnosed with MS. For more information, call 410-614-4823.