How can we treat progressive MS?

In recent years, disease modifying medications for relapsing MS have come on leaps and bounds. They work by dampening down the immune system in a number of ways: they might target the specific immune cells involved in attacking myelin, or stronger drugs might suppress immune cells more broadly. This might be more effective, but the trade off could be that weakening the immune system more broadly could leave a patient susceptible to other dangerous infections.

But, while these treatments are effective at reducing inflammation during a relapse, they have little impact on disability that builds up over the course of many years and lead to nerve death and neurodegeneration, leaving a big unmet need for reducing disability progression. To learn more about progressive forms of MS, and how we can treat them, Nick Cunniffe, clinical lecturer in neurology at the University of Cambridge, explains more…

Nick - Ultimately, we need to consider the nerve structure. Many people will be familiar with the fact that there's a neuron, and that has a long process called an axon, which is the main wire that the nerve fibre is going to send signals along. And then surrounding that is a lipid protein structure called myelin that's made by a cell called an oligodendrocyte. And that essentially is an insulating and protective structure around the axon. Now, when we think about progressive MS, the pathology is slightly different to the relapsing remitting MS. So the inflammation, the damage to both the myelin and the axons is much more compartmentalised. So rather than the immune system systemically becoming dysregulated with those immune cells getting from blood into the brain and damaging nerves, actually in progressive MS, the inflammation is proceeding unchecked, often termed as smouldering away within lesions, behind a closed blood-brain barrier. And that's important when we think about treatments for progressive MS, because many of our treatments won't get at that process.

James - And therein is the problem, of course. But do the disease-modifying drugs we use to treat relapsing MS have any effect on progressive forms of the disease, or are they completely ineffective?

Nick - We now know that it is absolutely in someone's interest to treat them with high-efficacy drugs early to prevent progressive MS, so we can sequence our drugs better, not just to prevent the relapses, to prevent progression. But as I mentioned before, the inflammation gets different as you get older, as you've been living with MS for longer. So how can we target that compartmentalised inflammation? A couple of papers were presented, a couple of trial results were presented, on the same compound called tolibrutinib. So this is something called a BTK inhibitor. And what this drug does, it's a small molecule, so it easily gets into the brain, and it has a role at suppressing the abnormal activity of B cells that have become activated, but really importantly, it also modulates the activity of microglia. So these are the innate cells that are contributing to that smouldering inflammation that's underlying progressive MS. And what they showed was that in people with non-relapsing secondary progressive MS, so a category of people in which there's no current treatment for, that this drug could reduce the rate of disability accumulation.

James - So those drugs will have a role to play in reducing that smouldering, behind-the-scenes inflammatory process. But are there other pathologies we need to be worried about when thinking about progressive MS?

Nick - Absolutely. So there is a natural inbuilt process called endogenous remyelination. So if you or I had a demyelinating insult in our brain, a group of stem cells, we call them oligodendrocyte progenitor cells, OPCs. And when we have demyelination, those cells will become activated, they will migrate to the area of damage, differentiate, so make more of themselves, and then they will start laying down myelin. That's what should happen, but it becomes less effective as we get older, but it becomes particularly deranged in multiple sclerosis as well. So we think the failure of remyelination or the failure of repair is one of the mechanisms by which more advanced disability develops, usually in people in their 40s and 50s who've been living with MS for a longer time.

James - So what can we do about it?

Nick - So we think that one of the main blocks to repair is differentiation of the OPC. So various different lines of research has been undertaken to try and understand the reasons why this process fails so that we can identify druggable targets to kick it into action. So several drugs that have either been novel or repurposed have been taken to trial to see if they can enhance this process and stick myelin back on nerves. And across several trials now, we've seen positive and encouraging effects.

James - That is obviously brilliant to hear, but I want to also, while I've got you, ask you about another promising line of research going on to help halt the advance of progressive MS. Could you give us an introduction, please, to neuroprotection?

Nick - If we're not considering remyelination, the other thing you could conceivably do is try and enhance the resilience of the underlying axon, the underlying nerve fibre. So we call that neuroprotection. Now, what we're doing here is lumping together many different mechanisms because there are lots of different reasons why an underlying axon will be vulnerable to degeneration in the long term. And all of these factors contribute towards that nerve fibre withering, dying, and that is ultimately going to lead to progressive disability. So ultimately, when we talk about neuroprotective strategies, we are talking about a factor that addresses one of those different mechanisms.