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"Paradoxical findings are often best — better, in fact, than when things turn out the way you expect." So says Moses Rodriguez, M.D., a Mayo Clinic Distinguished Investigator and professor of neurology and immunology in Rochester, Minn.
Three discoveries in central nervous system (CNS) repair and protection at Mayo Clinic highlight the truth of his statement. Each of the discoveries was made during investigations of Theiler's virus, considered one of the premier animal models of multiple sclerosis (MS).
Theiler's virus induces encephalomyelitis with chronic inflammation and demyelination and secondary axonal dysfunction in laboratory mice. It is a member of the picornaviruses, viruses for which there are no treatments and that in humans cause a range of conditions from the common cold to poliomyelitis and, possibly, amyotrophic lateral sclerosis (ALS).
In the late 1980s, Dr. Rodriguez and colleagues Larry R. Pease, Ph.D., chair of Mayo's Department of Immunology, and Arthur E. Warrington, Ph.D., in the Department of Neurology, were testing the theory that stimulating the immune system through immunizations with myelin would aggravate Theiler's virus-induced demyelination, which is similar to human MS.
Surprisingly, during their experiment, they found that rather than showing increased demyelination, the Theiler's virus-infected mice showed evidence of extensive remyelination. It was the first demonstration of naturally induced CNS repair. Their findings led to the now-accepted concept that the inflammatory process that induces demyelination in MS also induces some aspect of remyelination.
Equally surprising was the finding that the repair process they had witnessed was not caused by alterations in the immune response, but rather by molecular actions directed by natural antibodies against the surface of oligodendrocytes themselves, stimulating them to produce myelin. The agents of the observed remyelination were monoclonal autoantibodies (mAbs), which, rather than serve pathologic functions like conventional antibodies, serve normal cell processes.
Over the next several years, the team was able to isolate a human autoantibody, which they labeled monoclonal HIgM22. Unlike industry-synthesized antibodies, HIgM22 is a naturally occurring immunoglobulin molecule that is primitive in evolutionary terms and is the body's first and most rapid response, often referred to as the innate immune response.
Micrograph showing remyelination in the spinal cord of a mouse
HIgM22 was sequenced into a recombinant form (rHIgM22) in Dr. Pease's laboratory and was found to be as effective as its serum-derived counterpart in inducing remyelination in Theiler's virus-infected mice. The results showed that 60 to 80 percent of the animals' lesions were repaired.
Having manufactured enough rHIgM22 in conjunction with the University of Minnesota to take the drug to clinical trial, the team is now completing the animal toxicity testing required by the Food and Drug Administration (FDA) and has found no adverse effects. The researchers are writing an Investigational New Drug application for FDA approval to test rHIgM22 as a remyelination treatment for MS, a step required before a novel therapy can go to human clinical trials. rHIgM22 represents a completely unique approach to MS treatment in particular and to restorative CNS therapy in general.
In their search for other reparative autoantibodies, Dr. Rodriguez and the research team identified two new human mAbs that they named HIgM12 and HIgM42. Both of these molecules promoted in vitro CNS axonal extension and were able to rescue cultured neurons from laboratory-induced apoptosis.
Cells with fine structures of neurite growth
Similar to the mechanisms of HIgM22, HIgM12 appears to activate repair and prevent cell death through alterations in molecular signaling, not alterations in the immune system. Dr. Rodriguez describes the effects of HIgM12, stating, "When you place the autoantibody on the cell, you can actually see the axon growing."
HIgM12 has implications for possibly inhibiting apoptosis in stroke, spinal cord injury, primary motor peripheral neuropathies, ALS, Alzheimer's disease and other diseases that effect cell death and axonal destruction. Again in collaboration with the University of Minnesota, the Mayo Clinic team has successfully manufactured enough of the recombinant form of HIgM12 in pharmacological grade to test it in transgenic mice carrying the gene for one of the genetic forms of ALS. Animal tests are being conducted in Dr. Rodriguez's laboratory.
The 3Dpol gene, or 3D polymerase, is an RNA-dependent enzyme that has a central role in the replication and transcription of viral RNA. To better understand immune system viral resistance, Dr. Rodriguez and his colleagues infected groups of genetically altered mice with genetically manipulated segments of Theiler's virus.
Comparison of viral load in spinal cords of 3Dpol transgenic mice and normal mice
Their control group was a group of transgenic mice altered to express the virus-replicating 3Dpol gene and thus would be expected to be highly susceptible to the disease. Instead, they found that the 3Dpol transgenic mice were actually able to resist the virus. It appeared that the endogenously expressed 3Dpol gene was dramatically inhibiting viral replication. The mice had a 100fold to 1,000fold reduction in viral resistance compared with mice that were not expressing the 3Dpol gene.
The researchers then infected 3Dpol transgenic mice with different types of viruses and again found that the viruses did not replicate. As Dr. Rodriguez notes, "We have discovered something very fundamental about how viruses replicate, and if we can understand exactly how the 3Dpol gene works against viral replication, we may be on the path to a broadly effective antiviral therapy."
Taken individually or together, these findings may change the approach to treatment of progressive neurologic disease. As Dr. Rodriguez puts it, "The scientist wants to discover something that no one has seen before, so I look for experiments that are not working as expected, to try to find out why that is the case." As with many scientific breakthroughs in the past, tracing the origins of counterintuitive results has opened the way to rethinking previously held constructs.
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