Collaborative MS Research Center Award
$825,000; 4/1/04-3/31/09
Principal Investigator
Moses Rodriguez, MD
Mayo Clinic and Foundation, Rochester, Minn.
Collaborators
Allan J. Bieber, PhD
Charles L. Howe, PhD
Claudia Lucchinetti, MD
Slobodan Macura, PhD
James Maher III, PhD
Richard Pagano, PhD
Art Warrington, PhD
Mayo Clinic and Foundation
Purpose
To screen small molecules called aptamers for their potential to help define functions of myelin-making cells, and to explore the ability of discovered aptamers and larger antibodies to stimulate myelin repair. The team is also applying new technologies to help track the success of their repair efforts.
Summary
Although the body repairs some damage to nerve-insulating myelin that occurs in MS, this repair is insufficient. One strategy under study encourages internal "repair" capabilities of immune-system proteins called antibodies. Moses Rodriguez, MD, and colleagues have identified human antibodies that target and attach to oligodendrocytes (myelin-making cells). When given to mice with an MS-like disease, the antibodies promoted myelin repair.
Dr. Rodriguez has assembled a team of investigators to explore this exciting therapeutic opportunity further. The team is also exploring the therapeutic potential of "aptamer" technology. Aptamers are tiny, folded pieces of nucleic acids ("building blocks" such as those that make up the genetic material called DNA, and also RNA) which can attach to target molecules—such as oligodendrocytes—based on a lock-and-key fit. The Mayo group is investigating their ability to attach to and affect a variety of oligodendrocyte or myelin proteins—the "target tissues" in the immune attack in MS. Unlike many other larger molecules and drugs, aptamers are not recognized by the immune system as possible threats, and therefore have the potential to serve as diagnostic or therapeutic agents without being neutralized by the body's immune antibodies.
Dr. Rodriguez is employing the extensive "aptamer libraries" of biochemist James Maher III, PhD, an expert on screening and characterizing the function of aptamers. They are screening for aptamers that attach to the surface of oligodendrocytes or myelin components, and then studying the effects of these aptamers on human oligodendrocytes isolated in test tubes, and on samples of brain tissue damaged by MS obtained from Claudia Lucchinetti, MD, lead investigator of the Society-funded MS Lesion Project. Dr. Lucchinetti and colleagues have identified four patterns of damage that may exist in people with MS, and Dr. Rodriguez and colleagues are seeking to determine whether aptamers attach differently to myelin components within each pattern. This may indicate the potential of aptamers as diagnostic tools that can identify possible subtypes of MS.
Center collaborator Richard Pagano, PhD, an authority on the movement of lipids (fatlike molecules) in cells, is helping to investigate how antibodies that attach to oligodendrocyte or myelin promote myelin repair. Recent experiments indicate that these antibodies may interact with lipids on the surface of oligodendrocytes to induce repair. Now, the group is examining whether antibodies and aptamers affect lipids in oligodendrocytes in test tubes; the results may indicate that these molecules can affect the development of oligodendrocytes.
The Center team is testing the therapeutic potential of antibodies and aptamers in mice with MS-like disease, and is tracking the results using an imaging technology which Dr. Rodriguez developed with funding from the National MS Society's Pilot Research Program. This technology can detect and track the movement of myelin-making cells in the body, and the team is using it to observe the effects of aptamers and antibodies on such cells injected into mice with myelin damage. Slobodan Macura, PhD, director of Nuclear Magnetic Resonance at Mayo, is lending his expertise to this effort.
The elements are in place at the Mayo Clinic for a vital and collaborative community that integrates the proficiency of these basic scientists with experts in MS research. These include Allan Bieber, PhD (who is organizing the activity of the MS group along with Dr. Rodriguez), who studies genetic mechanisms that lead to spontaneous myelin repair; Art Warrington, PhD, whose expertise lies in the development of oligodendrocytes; and Charles L. Howe, PhD, who is developing a novel method of studying myelin formation.
Recent Progress
Dr. Rodriguez’s team reported in the February, 2007 Neurobiology of Disease on investigations of the factors involved in tissue damage in MS, for clues to developing more specific therapeutic strategies. They administered perforin, a mediator of immune cells that cause damage in MS, to some mice and not to others, and then induced MS-like disease in all of them. Mice lacking perforin experienced myelin damage, but not damage to the nerve fibers underneath. This suggests that nerve fiber damage is not just occurring as a consequence of myelin damage, but as a direct result of the immune attack.
These efforts can help to develop new treatment strategies for MS, and novel methods for tracking therapeutic success.