The Multiple Sclerosis Center at Johns Hopkins
The Johns Hopkins Multiple Sclerosis Center 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 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 has worked a decade
to show 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."
"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."
