Collaborative MS Research Center Award
Moses Rodriguez, MD
Mayo Clinic and Foundation, Rochester, MN
|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, Rochester, MN
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.
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.
Now, with funding from a Collaborative MS Research Center Award from the National MS Society, 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.
The power of these experiments is the potential of aptamers and antibodies to advance the care and treatment of people with MS. But these projects cannot be vigorously pursued without a strong collaborative effort. By gathering the talents of MS researchers and experts in new technologies, Dr. Rodriguez and colleagues can fully explore this exciting opportunity.