February 19, 2008 - By Mitzi Baker
Multiple sclerosis is not a single condition, but an ebbing and flowing of stages affecting the body's central nervous system. Recognizing that pattern, researchers from the School of Medicine have identified therapy targets that could lead to personalized treatments for patients at each phase of the illness.
Essentially, the team cataloged all of the brain-tissue proteins that they found were distinct to three discrete stages of multiple sclerosis
'This is a gold mine,' said Lawrence Steinman, MD, professor of neurology and neurological sciences. 'Knowing what proteins are most important at a discrete stage of the multiple sclerosis process is the first step toward being able to 'personalize' treatment.'
Steinman, whose team worked with researchers at the University of Connecticut Health Center, is one of two senior authors of the paper published in the Feb. 17 issue of Nature.
In the study, the team found many unexpected proteins involved in the disease progression. When they tested drugs that block two of these proteins in a mouse model of multiple sclerosis, the mice improved dramatically.
'If our hypothesis is correct, the findings can be directly applied to patients,' said May Han, MD, a postdoctoral scholar at Stanford and co-first author of the paper. She emphasized that researchers are still very early in the process of being able to tailor drug therapies for humans.
In multiple sclerosis, the immune system launches an attack against the myelin sheath surrounding nerve cells, causing them to misfire. The resulting variety of neurological disorders affects more than 2.5 million people worldwide, according to the Multiple Sclerosis International Federation.
When Han arrived to work in Steinman's lab, she suggested studying the amazing repository of multiple sclerosis brain samples still being stored in the lab freezer. The samples had come from Cedric Raine, MD, professor of pathology and of neurology at the Albert Einstein College of Medicine, who had collaborated six years ago with Steinman. Raine had obtained the samples from autopsies of patients with various stages of multiple sclerosis, and he had supplied a detailed analysis of the abnormalities.
Han proposed a novel idea: to use these carefully characterized slices to identify the protein changes between three major types of multiple sclerosis lesions seen upon autopsy - plaques from the acute stage (recent inflammation and damage to myelin), the chronic-active stage (long-term myelin damage and areas of recent inflammation) and the chronic-silent stage (no current inflammation).
Steinman recalled telling Han that it was a great idea, but that his lab didn't do proteomics, which is the large-scale study of protein structure and function. But Han had a secret weapon: Her brother, David Han, PhD, directs a proteomics analysis facility at the University of Connecticut Health Center. He is the other senior author of the paper.
They identified more than 1,000 proteins in each stage, creating the largest catalog of multiple sclerosis brain lesions to date. The enormous list of proteins became a bottleneck for the researchers. They used a computer program to identify which proteins were only present in each stage and came up with hundreds of unique proteins for each stage.
They picked two of the proteins found in the chronic-active phase for further exploration: tissue factor, which is involved in the coagulation of blood, and protein C inhibitor, which blocks the anticoagulant protein C. They chose these proteins for several reasons, including the fact that there are FDA-approved drugs that block those proteins, which would allow the researchers to tease apart what was happening.
Also, said Steinman, it was fascinating to explore these drugs, usually used for people with blood clots or hemorrhaging, in the completely different context of a role in a nervous system disorder.
Mice with the symptoms of multiple sclerosis showed improvement in the severity of their disease after being given drugs that block either tissue factor or protein C inhibitor. But treating a mouse is a far cry from helping humans.
'One of the stumbling blocks on this path to personalized medicine is that our samples came from multiple sclerosis brains,' said Steinman. 'Ordinarily, one doesn't stick a needle into a multiple sclerosis brain.' He said there are intriguing leads from other publications that suggest some of the proteins they found could be detected in cerebrospinal fluid.
'If a person had in their spinal fluid, using our findings as an example, an elevated level of protein C inhibitor, then a doctor could come into the room and say, 'We have a medicine that will fit you perfectly,'' Steinman said.
This work was funded by the National Institute of Health and the National Multiple Sclerosis Society.
Others from Stanford who contributed to this study were: graduate student Jordan Price; postdoctoral scholar Shalina Ousman, PhD; William Robinson, MD, PhD, assistant professor of immunology and rheumatology, and Raymond Sobel, MD, professor of pathology.
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