Q: Are current therapies effective in providing neuroprotection in relapsing-remitting MS and primary progressive MS?

It is difficult to answer that question because we do not have very good definitions, biomarkers, or methods to measure neuroprotection. We do see that patients who are treated with currently available therapies for MS, especially those that are highly effective, have improvements in outcomes associated with disability. Improvements in outcomes, such as measures of brain atrophy or some biomarkers associated with neurodegeneration, may indicate a slowing of probable neurodegeneration, but the degree of therapeutic benefit that can be attributed to anti-inflammatory effects versus true direct neuroprotection is still largely unknown.

With MS, there are many inflammatory cells in the brain, and, as long as you have the inflammation, it is not like a spinal cord injury or a stroke where the initial insult is gone. There is the initial insult and then one observes the consequence of the injury. In progressive MS, we are trying to stop the inflammation and provide neuroprotection. There is early axonal dropout, and attempts to remyelinate do not make a lot of sense unless you have very effective methods of stopping the inflammation. Using alemtuzumab, a drug that is highly effective at immunosuppression, and adding neuroprotection at that point would make sense. But alemtuzumab would have to be combined with a drug that is very effective in stopping the inflammatory cascade in the central nervous system. Dimethyl fumarate also blocks nuclear factor kappa B (NF-kappa B), and approximately 18% of the genetic variants are in the NF-kappa B pathway. So, the drug may be working by blocking NF-kappa B activity. Recent data suggest that the drug may be working by blocking glycolysis.

Fingolimod may have neuroprotective effects, particularly through glial cells such as oligodendroglial cells and astrocytes, changing the profile of astrocytes to produce anti-inflammatory, neurotrophic effects. Biotin is an important co-factor in myelination and for oligodendrocytes, and it may well protect against this so-called virtual hypoxia that results in axonal death. An early study indicated that high-dose biotin therapy improved results for the Expanded Disability Status Scale and/or the timed 25-foot walk in 12.6% of patients with progressive MS; however, a larger phase 3 trial of greater duration would be needed to corroborate these initial positive findings. Another compound is dimethyl fumarate, which has been suggested to work through the Nrf2 pathway. The University of California, San Francisco, generated a Nrf2 knockout mouse, and dimethyl fumarate still worked in the experimental autoimmune encephalomyelitis mouse model. I do not know how dimethyl fumarate acts, but, presumably, it does not act through Nrf2.