Our Animal Models for Multiple Sclerosis Research

Recently, Dr. Zamboni invited scientists to create new animal models for MS research due to the limitations of the current EAE (experimental autoimmune encephalomyelitis) animal model in answering questions about the efficacy of CCSVI.

In June, Rusty Bromley (COO of the Myelin Repair Foundation) responded to an article titled “Could MS Doctors be Treating the Wrong Disease?” by Dr. Julie Stachowiak on About.com:Multiple Sclerosis. His response below details our own concerns with relying on the EAE model:

MS research has relied heavily on the EAE model and yet virtually every therapy that worked in EAE has not been successful in the clinic. Conversely Tysabri didn’t work very well in the EAE model but has been very successful in people with MS.

The Myelin Repair Foundation is always keeping in mind that animal models are just that, models, not the real human disease. While the MRF does use two different EAE models we are very conscious of their limitations. Because of those limitations we also use other animal models that do not rely on activated T-cells to damage myelin.

The referenced article makes a very good point that the immune response in MS, while it certainly causes significant damage in MS, may not be the underlying cause of the disease.

When the MRF began research there were three dominant animal models of MS, all of which relied on the immune response to develop a MS-like disease. Studying demyelination and remyelination in these models can be confounded by the effects of inflammation. In order to study demyelination and remyelination directly without significant inflammation chemicals could be added to the animal’s food or injected into the brain or spinal cord to create a lesion. The damage that resulted was not limited to the myelin-producing cells and was spontaneously repaired fairly quickly.

One method for studying the effect of a particular target on the myelination or demyelination process is to genetically engineer mice or rats so that the gene for the target of interest can be induced to “turn on or turn off.” There are a variety of ways to do this and the MRF team has created several of these animals to study the affects of target specific genes on myelination.

While all of these methods have been successfully employed by MRF researchers in identifying new treatment targets, none proved to be the ideal compliment to the immune models for studying demyelination and myelin repair. Recently, MRF researchers have developed two methods for selectively killing oligodendrocytes, the cells that produce myelin so that the effects of demyelination and repair can be measured.

In one case mice are genetically engineered so myelin-producing cells can be killed throughout the brain and spinal cord. It then takes 30 days for the axons to become completely demyelinated and another 30 days for repair to reach a maximum level. During this process animals exhibit clinical symptoms that can be quantified to track progress of the myelin damage and repair. Since the damage and recovery process is slow, new candidate therapies for myelin repair can be tested in this model and the impact can be easily measured and compared.

In a second model, genes can be transferred into oligodendrocytes that react with a chemical compound to drive death of these cells in a specific location. This method enables MRF researchers to create myelin damage in various areas of the brain and spinal cord allowing them to compare the effect of potential therapies in different regions of the CNS. These two techniques allow for much more precise experimental control and easier measurement of myelin damage and repair than the methods that were available when the MRF began research in 2004.

Developing new animal models, especially those that require genetic modification, is difficult and time consuming. The model of systemic demyelination described above required four attempts before the right combination of genes was achieved and selective elimination of oligodendrocytes was possible. Each attempt required a tedious process of transferring genes and breeding animals before the mice could be evaluated.

The benefits of success are well worth the investment as these models can now be combined with the traditional EAE models to evaluate new therapeutic approaches and may provide unique insight into the myelin repair process that would not be evident with EAE alone.

Tags: animal model, bromley, debate, EAE, experimental autoimmune encephalomyelitis, freedman, hypothesis, immune response, Immune system, inflammation, Mark Freedman, ms research, myelin repair foundation, Paolo Zamboni, remyelination, research, t cells, tysabri, zamboni

This entry was posted on Tuesday, December 8th, 2009 at 3:30 pm and is filed under Uncategorized. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.