The Professor in UCLA's Department of Neurology and Director of the UCLA MS Program spoke about disease-modifying therapies that would complement anti-inflammatories by targeting neurodegenerative processes.
Rhonda Voskuhl, MD
Rhonda Voskuhl, MD, who delivered the Kenneth P. Johnson Memorial Lecture at a meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) held in Dallas, Texas, sat with NeurologyLive to speak about an area in multiple sclerosis that has little success: creating treatments to target cells within the brain.
Voskuhl shared her approach, which isn’t to look for a one size fits all therapy, but to try and develop disease-modifying therapies that would complement the anti-inflammatories by targeting neurodegenerative processes. She added that the holy grail for why researchers haven't been able to find more neuroprotective treatments in MS and other diseases, is because researchers haven’t strictly focused on trying to optimize one disability at a time.
Rhonda Voskuhl, MD: In MS we've made great strides as a field in finding anti-inflammatory treatments which target t-lymphocytes, b-lymphocytes, macrophages, and this is excellent because this is shown to reduce relapses dramatically and this has changed people's lives, however, what we really have not delved into successfully yet are treatments to target cells within the brain, astrocytes, neurons, microglia, oligodendrocytes, and it is difficult to study these cells but they can be done.
Our approach has been to not necessarily assume that we will find a one size fits all for all the cells or even the different regions of the brain. Our goal would be to try to develop disease-modifying therapies that would complement the anti-inflammatories by targeting neurodegenerative processes, and the way to do this I think is, unfortunately, going to involve perhaps disability specific neuroprotective treatments.
We may not be able to find a one size fits all, and the reason is because the visual pathway differs from the walking pathway, which differs from the cognitive pathway and so on, they differ with respect to some cell types, some are shared but some are different, some neurotrophic factors, oligodendrocytes, microglia, and astrocytes differ from one region of the brain to the other.
I think the holy grail for why we haven't been able to find more neuroprotective treatments in MS and also other diseases, is because we haven't been strict enough in focusing on trying to optimize one disability at a time—if they differ it’s kind of unlikely to have a silver bullet to just fix all of them and maybe the way to do it is to fix one at a time, using the same approach, but the details will be different, it would be optimized for vision and it may have some effect on walking or no effect on cognition, or maybe something optimized for cognition may have no effect or lesser effect.
This important at the discovery level, as I think it needs to have region specific and cell-specific gene expression optimized to reverse abnormal gene expression in the walking pathway, vision pathway or cognitive pathway.
This really has implications for clinical trials because you wouldn't want to include people that had inclusion based on a composite score like and EDSS or an MSFC or even better and better composites, I don’t think the goal is to get a better composite, I think the better idea is to not to lump them together at all but keep them separate, because biologically and scientifically they are separate, and so let's not lump them together in our inclusion/exclusion criteria. Let’s just start over and say, this is going be for cognition and therefore to get another trial you have to have cognitive problems and you can have other things too, but you have to have cognitive problems that we're going to try to make better. The primary outcome measure of the trial, not just the exclusion or inclusion criteria, can't be improvement of composite because you'll dilute out the effects you might have if you found a really good drug for one disability by the partial or lack of effects on other disabilities.
The idea is let's just fix one first and optimize it and make the trial fit what you did at the basic discovery level, at the clinical level.
In order to do this, we're using a very complicated chronic progressive model of MS that involves mice that have progressive phase of MS because we want all of these things to be going on at once, but then we genetically go in and look at gene expression just in astrocytes of the spinal cord or oligodendrocytes of the cognitive area or neurons of the visual pathway.
We were going to do cell-specific and region-specific gene expression, which will then give us a target because wow this comes up and it's not in the normal and it’s associated with disability in that particular pathway, and we come in with treatments and reverse those and the next thing is to go in and design the trial that will fit the basic discovery based on gene expression.
To that end what we did find that we published in the proceeds of the National Academy of Sciences this year, was that it was striking there was a decrease in cholesterol synthesis genes, in astrocytes in spinal cord. That is surprising and when starting to think about the implications of that, what would that do, and the reason I think it's important is because while the damage to the myelin and axon and synapses in MS again are due to lymphocytes, macrophages, etc. the reason we don't repair could be due in part to the fact that astrocytes are not making cholesterol, which then can't be transported to oligodendrocytes to put into new myelin or to neurons to put into new synapses—and so you can't remyelinate and you can't have synaptic plasticity when you get this damage.
The idea then would be to increase cholesterol synthesis in astrocytes because that was the abnormal gene expression you would want to reverse and there are drugs that can do this but the bigger implication today is what happens when people are on statins to lower cholesterol synthesis in the periphery, and that is good, it's great for preventing heart disease and strokes and those comorbidities. There's one trial in MS were they're trying it and based on some of its inflammatory effects, it was looking like it might be promising.
I would just say because of this information, we might need to think about looking very closely if any of the disabilities could be worsened, it's just something you would want to monitor closely in those trials and really delve into the role of cholesterol being synthesized in the brain and what effect this has on repair and disability. That's where it's led.
Transcript edited for clarity.
Noriko Itoh, Yuichiro Itoh, Alessia Tassoni, et al. Proceedings of the National Academy of Sciences. 2018;115(2):E302-E309.