Luke Lairson, Scripps Researchers Institute in California
MS has a pattern of remission and relapse; this is because the disease flares up periodically, causing damage to the nervous system, which then slowly repairs itself. But it doesn’t completely fix the damage that’s done, and this leads to progressive worsening of the symptoms.
Chris Smith spoke to Luke Lairson from the Scripps Research Institute in California where he’s found some drugs that might be able to stop and even reverse this.
Chris - So, tell us about the approach you've taken.
Luke - So, we sort of heard MS is a disease which is associated with primary demyelination of axons which leads to neural dysfunction and as you've just described, the disease is characterised by relapsing and remitting phases, and ultimately, we get progression of the disease. And what's known is that during the remitting phases of disease, there's a population of stem cell derived cells termed oligodendrocyte precursor cells which are recruited to sites of injury and subsequently, differentiate to a mature cell that can remyelinate the damaged axon.
Chris - So, just to translate this slightly, you've got these stem cells sitting in the nervous system that are capable of giving rise to the same cells that make the myelin that gets attacked in the disease and which goes away during the inflammation, and that those stem cells can potentially give new cells to remyelinate and repair damage.
Luke - Exactly, right. And so, what's known from looking at the chronic lesions of MS patients, of the histopathology of those lesions is that, during the progressive phases of the disease, there's still an abundant presence of this precursor cell. However, they're found to be in this intermediate halted state of differentiation so they don’t fully mature to a cell that can repair the damaged axon.
Chris - So, it’s a bit like you're in the garage and you've got a car that needs repairing and there's all the spare parts there, but they're not just being put onto the vehicle.
Luke - Right, exactly. So, what people have sort of proposed for the last decade is that an effective complimentary approach to the treatment of MS in conjunction with immunosuppresor strategies as we’ve heard about would be to identify agents that can directly induce the differentiation of those precursor cells which are in this halted state of differentiation.
Chris - So, how did you approach that? How did you do it?
Luke - So, the approach we’ve taken which people proposed to do is, we used an unbiased high throughput microscopy cell based approach. We took primary cells from rat optic nerve and developed assay conditions where we could mimic that halted differentiation and then screen against that 100,000 compounds to look for potential drug candidates that induce the differentiation to a myelin basic protein positive mature oligodendrocyte fate.
Chris - Basically, you grow some cells in the dish that could make myelin if they were so inclined. You then chuck on up to 100,000 different chemicals. So, in other words, you're doing this many, many times to see if any of those chemicals make those cells go back into a state where they want to make myelin and then you can go, “Aha! That might be a potential drug to repair lesions in MS.”
Luke - Exactly, right. And so from this, we actually identified a number of compounds. Several of which had not been characterised before which belong to a class of so-called neurotransmitter receptor modulating agents, which effectively induced OPC differentiation in vitro. And so, we decided to fast track the analysis of these compounds because a number of them are actually approved drugs which are known to be centrally acting, i.e. they can get into the spinal cord or the brain. And so, they have the potential for rapid progression to clinical development.
Chris - What drugs did you find?
Luke - The most efficacious compound we identified was an approved drug called benztropine which is currently used for the treatment of Parkinson’s disease. Using pharmacology, we’ve determined that the activity of this compound is dependent on antagonism of a specific neurotransmitter receptor, the muscarinic receptor.
Chris - In other words, by blocking up that receptor, it makes the cells become active.
Luke - Right and that's consistent with the finding that was reported by an Italian group last year where they showed that activation of that receptor actually induces the proliferation and inhibits differentiation of this precursor cell.
Chris - And have you got any evidence at least in animals if nothing else that if you give this agent that it can remedy the damage done in MS?
Luke - Once we identified this compound and realised that was an FDA approved drug that would work in the central nervous system, we decided to evaluate it in vitro and in vivo using mouse models. So in vitro, we showed that we could in fact remyelinate existing axons in a co-culture experiment. And then we looked at the drug’s activity in two mouse models of demyelination and remyelination. The first one is a relapsing remitting model, inflammatory model of MS known as the PLP-induced EAE model. We found that benztropine had a dramatic effect at decreasing the clinical severity in this disease. With efficacy, that was comparable to or better than existing standard care immunosuppressive drugs. We then went on to look at it in an additional model which is a non-inflammatory toxicity model known as a (24:56) model. And again, we found that the drug had a dramatic effect on enhancing the rate of remyelination in vivo in MS.
Chris - It must be reason to be positive then, Luke. Thank you.