Portia 

Hello everybody and thank you for joining us on our latest webinar. 

We’re really lucky to have Dr. James Sleigh with us today and we’re going to have a chat about current research and future treatment. We’re going to talk all about treatments that are in the research phase, what’s coming through for people living with SMA. So, I’m Portia and I’m Head of Advocacy and Community at SMA UK and I’ll hand you over to James who will tell you a little bit about himself. 

James 

Hi everyone, my name is James Sleigh and I’m a professor of peripheral nerve disease at the Queen’s Square Institute of Neurology, which is University College London. And I run a laboratory working with mouse models and stem cells on a condition similar toSMA known as Charcot-Marie-Tooth Disease. But I’ve also been involved with SMA UK since 2011, so when it was the Jennifer Trust, as your research correspondent.So, I’ve been around for a while. 

Portia  

Yes, and James checks all our posts on new and upcoming treatments to make sure that they’re accurate and understandable. So, you work in the lab James. Am I right?  

James 

I do. 

Portia 

So, when all these treatments first start coming through, you’re the guy and people like you working in the labs looking at test tubes and mice? Any other animals or is it just mice? 

 

James 

So actually, there’s a range of different organisms we use as scientists to sort of understand different diseases and cellular processes. For example, I started my science career working with a little nematode worm called C. Caenorhabditis elegans, or C elegans. But there’s also Drosophila models for SMA as well. But I think the main workhorse is the mouse. 

Portia 

When you say models, what does that mean? 

James 

So when we’re trying to study a disease like SMA, we require sort of animals or cell lines that will have features of the disease. And those features can either be the genetics. So, for example, we know SMA is caused by loss of SMN1 gene function. So, if we can create models that also have loss of that gene, we can potentially 

So, SMA is a little bit different in that there are two genes that produce the SMN protein. We have SMN1 and SMN2 and actually most organisms only possess an equivalent of SMN1. And so a little bit of different genetics have had to sort of been, a little bit of 

engineering has had to occur in the mice to be able to better model human SMA. Because we know that if you remove SMN1 completely, and if there’s no SMN2 and no SMN protein at all, that’s completely lethal. So, there’s no survival of mice, for example, if you remove their SMN gene completely. 

But they have been genetically engineered to, there’s many different models, but some of them have been engineered to express a very low level or have a very low level of the SMN protein that allows them to survive up to two to four weeks, that allows us then to study the processes that go wrong in the disease. 

Portia 

Poor old mice. 

James 

But it’s all for a good cause. 

Portia 

Could you tell us a bit about how treatments go from someone’s idea to an actual physical treatment for people living with it? 

James 

I think the answer to that is quite a long answer. And I think the best way to break it down is into the parts that we’ve got here on this slide. We have the preclinical side, so everything done in the laboratory to really provide sufficient evidence that a treatment is having a beneficial effect in the models that we work with. 

So, for example, in mice, like I said, they normally survive for two to four weeks, 

depending on the model and sort of testing treatments in that mouse. If we’re getting things that are really sort of extending their survival and improving features of their neuromuscular disease, then that can sort of then begin to go into additional testing in humans. And so generally that involves three different phases of clinical trial. 

We have the phase one, phase two and phase three, and they’re sort of looking at different elements of the treatment. 

So, phase one generally is looking at sort of the, these are first in human studies generally, and they’re looking at the safety of putting a treatment into a human being. And this is often done in healthy volunteers, and it involves sort of 20 to 80 people. 

And if all of the safety, if the drug is perceived as being safe, it will then transition into phase two trials, which are still looking at safety, and that’s a theme that occurs throughout these tests and these trials because obviously anything going into a human, we want it to be ultimately safe. 

But phase two, we’ll start to look at potentially different doses and will give us a bit of evidence as to whether a treatment is effective, not fully, and that’s where phase three comes in. That’s really when more individuals are incorporated into the trial and more sort of evidence and data can be provided to assess the efficacy or the effectiveness of the treatment. 

An important feature of clinical trials in rare diseases is they are quite tricky to perform because often the patient populations are a lot smaller, for example, than a particular cancer or something like that. So, there are a few subtle differences in sort of how drugs for conditions like SMA would be tested. 

And then I suppose once that’s why once it goes to marketing so if you take our two drugs,  the SMN two drugs that we have nusinersen and risdiplam so they’ve gone to patients but we’re still collecting data. 

Portia 

Is that something that’s usual for rare diseases? 

James 

That’s a good question and I don’t fully know the answer to that one. But I would say that yes, once a drug has been approved by the different bodies, for example in the US, the FDA, in Europe, the EMA, there are real world studies that clinicians throughout the world are testing these therapies and really confirming in different populations of patients or different genetic backgrounds in different countries, for example and just really providing additional evidence that a treatment is still effective and still safe. 

Portia 

So apart from the numbers in rare diseases, are there any other challenges for researchers in fields like SMA, rare? 

 

James 

So I guess a lot of it is understanding the genetics underlying a rare disease. For example, there are examples of diseases out there where you’ve got maybe a handful of people in the whole world who have it, they’ll have very particular clinical symptoms, but they don’t understand at the time what the underlying gene is that’s driving that. And for example, the SMN genes were identified in ’95, I think. And prior to that, we didn’t really sort of have a genetic diagnosis for the disease. And I think that’s something that makes it difficult to study it. Because if you don’t know the underlying genetics, you can’t really create the models in the lab. 

There are more than 10,000 different rare diseases. You know, the, what you call it, the definition is it’s a disease that affects less than one in 2,000 people in the EU. And it is obviously one of the first rare diseases to have the underlying gene identified. So, I guess in some ways that is lucky. But yeah, I know it’s obviously been very beneficial for sort of how SMA has been studied in the lab, but then also the development of the different therapeutics for the disease. 

So just going back to the major challenges, I think just funding, I’m a scientist, I’m always going to say funding is difficult, but when you have diseases like cancer affecting one in two, heart disease affecting one in three, it’s difficult then to gain funding for conditions that affect one in 10,000, one in 20,000, because, you know ..They’re not less important by any stretch of the imagination, but they affect fewer people directly and indirectly. So, it makes sense that that is the case, but it’s a difficulty of the situation. 

Portia 

It’s always difficult with money, isn’t it? 

So let’s have a look. Moving on from your clinical trial phases to having a look at SMA drugs in particular that are coming through the pipeline. 

James 

That’s quite a small diagram, but on there, we’ve got at the top there the three SMN targeting treatments that are already available. And we can see that arrow goes right across to patients and we’ve got Novartis’s Zolgensma and risidiplam from Roche, one in a tablet form now, which is really exciting. 

Portia 

Can you explain just really quickly the differences in how these three treatments work? Yeah, so I guess the first thing to highlight is the similarities in that they’re all trying to restore levels of SMN protein in the condition because that’s ultimately what drives the lower motor neurons being impacted by the disease and the mutations. 

When it comes to differences, so Spinraza or nusinersen is an antisense oligonucleotide or ASO. And basically this is a small bit of man-made genetic material 

 

essentially, that recognizes something that’s required in the body to make the SMN protein. And it impacts how that intermediate message is read and ultimately makes more of the SMN protein. 

And so, this is a drug that’s injected quite frequently into the space, into the fluid that bathes the brain and the spinal cord. So, it’s quite an invasive treatment. 

And similar to Spinraza, we have Evrysdi or risdiplam. And that is a small molecule drug that can be ingested orally in tablet form now, but also in oral solution. And that is a drug that also targets this intermediate message between the SMN gene DNA and the SMN protein. And sort of it affects how much the SMN protein is made essentially. 

And then finally we have, I’ll just go, I’ll finally talk about them. 

And then we have Zolgensma or onasemnogene abeparvovec, which is a gene therapy that makes use of harmless non-replicating viruses to package up the SMN1 gene and deliver that currently through intravenous injection, so directly into the blood so that this virus travels around the body, gets to different cell types and starts to express and produce the SMN protein to restore that that’s missing in patients. 

Portia 

So, two questions actually. For the Spinraza versus risdiplam, I mean, that’s always a, which one do we choose? They both work on SMN2. My son who’s got type 1 SMA, he’s a Spinraza patient, mainly because when he was diagnosed, that was the only one available. I’m too scared to switch him to risdiplam because personally I’m like, oh, I don’t know if it works, why rock the boat? And I have this thought that if it goes into that fluid, like that’s going straight to where it’s needed. 

And the risdiplam you’re taking orally, so it kind of goes all around your body. And with my mum hat on, I’m thinking it must work better if it’s going straight to where it’s needed. 

Is there any mice lab anything or is that just me making it? 

James 

It’s a valid concern, you know, swapping from one treatment to another, I can imagine, would be a very difficult decision to make. 

Direct comparisons of these different approaches haven’t really been done in patients, probably because you have lots of different drug companies involved and I don’t think that would necessarily easily work to be able to assess them side by side. I think what I will say though is that they all do work very, very well and they all sort of have the same sort of general sort of strategy and mechanism through which they work to boost those levels. 

You know, I guess it’s a personal decision as to sort of the way that they’re delivered. 

 

You know, a single intravenous injection sounds great, you know, early on with the Zolgensma, but you know, the negative of that is that you’re putting a…a very large amount of viruses into young children. So that’s sort of a potential negative of that. 

 

With the Spinraza, again, it’s getting directly to where you want it, so the motor neurons in the spinal cord. But ultimately, it takes an injection every four months. 

 

And finally, with the Evrysdi, it seems on the surface great because you can just take it, sort of not thinking about it too much, it’s sort of going around the body and maybe it’s  not resulting in the same increase in SMN levels within the motor neurons as you would as you got the direct injection. I don’t know that for sure. 

Portia 

I would guess based on the clinical trials that they’re relatively equivalent. 

James 

Yeah. But then I guess there’s also something to consider is that I guess the more severe SMA is, so the lower the levels of SMN protein in a patient, definitely in mouse models, the more…the more different tissues that might become affected. 

So, there’s quite a lot of evidence from mice that as you slowly reduce levels of SMN protein using different mice and different models, they become more severe and there’s a chance for other tissues to be involved in the disease. 

So, with something like Risdiplam, with it getting around the body, it might then also have more systemic positive effects as well.  

Portia 

OK interesting 

James 

Although that does definitely seem to be less the case in patients than it does in mice, but there is the potential for that. 

Portia 

That’s really interesting. And with the gene therapy, does it literally replace your SMN1 gene so that then if that person grew up, had their own children, it means that they wouldn’t pass on the disease anymore? Does it like… 

James 

No, that’s not the case. 

So, basically these viruses are based on something called the adeno-associated virus, or AAV, which is essentially a helper virus found naturally. OK.  It’s not necessarily a lab-created thing. And what it does, once it gets into these different cells, it creates these circular DNA structures that I think they’re called epizomes. And essentially that’s where the SMN gene is held and used to produce the SMN protein. So there’s no integration whatsoever into the human genome, which is absolutely essential because if you were to take a virus that was to insert DNA into your DNA, there’s the chance that that would then impact the function of other genes that you have in different cells. So, you really don’t want to do that. So, you really want to make sure that it’s creating these sort of stable DNA structures that can continually produce the SMN protein, but then they won’t be inherited. 

Portia 

So, there’s no chance of it being passed on in that sense. 

James 

Right. 

Portia 

So…On the pipeline, if we have a look, we have this new addition that is creeping towards the MHRA EMA approval, which is the intrathecal gene therapy. Could you tell us a little bit about how that differs to the current IV treatment and why I’ve heard it’s considered safer for bigger children and adults, which is exciting? Explain that a little bit. 

James 

It’s very much so.So going back to these viruses, we have to put a lot of them in to the children to be able to get a therapeutic effect. I don’t know the numbers, but we’re talking millions and millions, if not billions and billions of these viruses, the dose is related to how heavy the patients are. And so…Definitely with older children, they get bigger, they get heavier, more and more viruses are required and it becomes a prohibitive number essentially and a dangerous number to sort of be giving to people. 

And so the idea of the interthecal injections is that we can use a tenfold or sort of ten times less of the virus directly injected into the nervous system, which again could have its potential side effects and negative elements, but at least in the trial so far, I don’t think there are any sort of severe adverse effects. 

So it does seem like…It’s a useful approach for treating of slightly older patients as well. 

 

Portia 

I have even more treatment decisions to make now. Potentially, potentially. It must be a very difficult one.. Especially when there’s literally no long-term evidence and no evidence in type 1 in this case because there were no type 1s in the trial as well or older than 17s and I think that they’re going for a license for anyone over 2 with SMA. So that would be interesting to what happens. 

James 

It will be, and I guess it makes sense because at the moment, Zolgensma is very restricted in who it can be delivered to when it’s given IV. And I think it has great potential. 

So with these viruses, you inject them into the blood and they can get to different cells in the body, but they tend to like to go to particular places. So they can go to the liver and you can get sort of liver issues sometimes when you have so many. 

I suspect in the future, we…In the lab, people have sort tinkered with the proteins that make these viruses so they can target more specifically different cell types. So for example, you might be able to change the surface of these AAVs so they go to motor neurons better. 

So actually, if you do that, you might then be able to reduce the load and then also still deliver intravenously. But that’s something potentially for the future. But I suspect people will continue to work on these. 

Portia 

That’s cool. 

And there’s also this issue of antibodies.So you have to have a blood test to see if your antibody is at a fair level to accept the virus. I’m presuming that for the older children and adults, there’s going to be more likelihood that you won’t be able to have it because of antibodies. 

James 

Definitely and I’m sorry I didn’t mention that as I mentioned though that the virus is sort of found naturally in low levels and you might become exposed to that and you know I think 50 % of people generally show a response to this and have been exposed to it and when that’s the case it’s much less likely to work essentially because the body recognizes it immediately as being foreign and it mounts an antibody response much more quickly than it does if you’ve never sort of been exposed to it before. 

Portia 

Okay, so there’s quite a high chance that quite a lot of people won’t be able to get access to this because their antibodies will be too high because they’ve had… 

James 

Yeah, I suppose they’re sort stratified out of the trial because they’re sort of exclusion criteria. 

Portia 

Do you think in the lab there’s any way that you can reverse those antibodies to give more people a chance of getting gene therapy? 

James 

You can immunosuppress, so restrict your body’s response to foreign invaders, but as I just made that sound, it’s probably not the best thing to do, especially if you have respiratory issues and you’re sort of prone to infection. If you’re limiting that even further, I don’t think that’s a good idea. But you know, that’s why then, and it’s really nice that there are alternative approaches, because if you can’t have Zolgensma, then you have the risdiplam and Spinraza treatment. 

Portia 

So as a Mum on lots of SMA social networks and everybody is always talking about how they want dual therapy. It’s real big conversation topic in the SMA community. And I know there are trials ongoing, I think, with some dual therapy ideas. What’s the sort of lab evidence that you might get or you might not get a better outcome by combining either an SMN1 and SMN2 targeting or two of the SMN2 targeting drugs? Do you think there is……a way to? 

James 

Yes. I guess, I’ll split that up into a couple of different elements, I think. 

So first, there aren’t many studies really looking at the combined treatment of animals with multiple SMN dependent therapies. So for example, you don’t really have ASO Spinraza being added with the gene therapy. And I don’t think that generally will happen in patients either, mainly because they are trying to boost the levels of SMN. They’re both trying to do that. 

Now they might do that in slightly different parts of the body. As we mentioned, know, the risdiplam can go into certain areas, maybe the ASOs can’t, and then the ASOs can get, or the viruses can get to certain cells that maybe the risdiplam doesn’t. 

So there’s a potential for sort of synergism or positive sort of interactions between the two, but probably not going to have…that much of an additive effect. 

1. OK. Andthere’s also some hints from the laboratory that if you really, really boost levels of SMN protein long-term in mice, for example, to very high levels, it can potentially have negative effects.  

Portia 

Interesting 

James 

And so by combining the two, you might want to try and avoid that.B ut when it comes to sort of alternative ways of combining therapies, you know, on the one hand, we know what causes SMA and that’s loss of SMN protein. So the therapies that are really sort of trying to target that, they’re targeting that element of it.But oftentimes the SMN is being put back not at the perfect time, so i.e.as early as possible, and therefore the neuromuscular system is not going to be exactly as it would be in somebody without SMA. OK. 

And so these alternative approaches are really trying to support the neuromuscular system in how it functions. 

Portia 

So its not  a case…loads more SMN the better of your outcome. It’s not. It’s not that. 

James 

Not necessarily. Um, there’ll be a level where, know, if you take a cell and you, and you pack it full of any protein, there’ll be a, there’ll be a, there’ll be a point at which that’s too much for the cell to sort of look, to be able to survive. Even if it’s sort of missing in the first place or very low in the first place. 

We often think more is better, but actually with a lot of these proteins and genes and how they’re expressed, there’s often like a Goldilocks window, you know, too little is not good, not good, but too much is also not good. And you’re really trying to get it into that window. 

Portia 

Which is a lovely segue into my next question. Looking at the purple section of this chart where it says combined treatments. So could you tell us a bit more about treatments that maybe are potentially really great if you combine them with the SMN targeting treatments? 

James 

So at the moment, I guess the SMN independent treatments will be things that either target muscles, so muscle support, or they’ll target the lower motor neurons, which are the main sort of nerve cell type that is affected in the condition. And that’s often called neuroprotection. And at the moment, the compounds and the drugs that are being tested in combination with SMN dependent treatments are really targeting the muscle. 

So we have…I can never say these names. We’ll call it SRK-015 or Apitegromab. Then we have Taldefgrobep alfa and Emugrobart. These are three different treatments that are targeting a protein called myostatin, which is expressed and found in muscle. 

And then we have NMD670, which is, it targets a different protein called CLC-1, but that’s also a muscle found within muscles and is a means of supporting the muscle as opposed to the nervous system directly. 

Portia 

I remember hearing about these anti-myostatins a long time ago, probably maybe like six years ago, probably when they were coming out of pre-clinical. And I was really excited because I thought, my goodness, this is brilliant. We’ve covered the SMN and now we’ve got something that could like regrow his atrophy muscle and it will all start working again and it will be brilliant. But as this comes through, I’ve realised that it’s not a hulk, sort of miraculous hulk….it’s not a steroid, it’s not…Can you explain a little bit about how it works and maybe the expectations that we might have? 

James 

It’s a little bit funny that you mentioned the Hulk, because if you lose the function of myostatin in mice, in dogs, in cows for example, you get really muscular Hulk-like animals. And that’s because myostatin is a protein that is basically the brakes on muscle production. And it ensures that you don’t…have these hypertrophied really, really big muscles because ultimately that’s clearly negative because if it wasn’t, it wouldn’t have been selected for an evolution. 

It’s important to make sure that we don’t have too big muscles for our skeleton, for example. It stops them from growing too big and therefore anything that’s inhibiting that protein and stopping its normal function will remove those breaks a little bit, either fully or a little bit and therefore the idea being that that will then lead to improved muscle growth. 

Portia 

Okay, can it fix atrophied muscles? 

James 

I guess, I mean, I think the answer is yes in the sense of we know from some of the clinical trials so far on these different myostatin inhibitors that when combined with SMN-dependent treatments, they do seem to have an additive effect in patients. And so I think, you know, they’ll be being delivered at time points that are after a disease, the SMA has occurred. So in that sense, I think yes. 

Portia 

Okay. 

James 

But there will be a point at which atrophy perhaps is too much for them to actually probably have an impact and like a lot of different conditions stabilising the disease sometimes is what can be achieved with these treatments rather than sort of creating Hulk as you put it, you know, so I think 

Portia 

I know with my son, he’s now nine, he’s got to a point where he’s very much stabilised on his Hammersmith Physio assessments. We maybe go up one point, down one point, but there’s not really much change. And I suppose maybe an anti-myostatin isn’t gonna, you know, woo, take him up, but it might keep him there or stop him dipping. 

James 

So I know as you get bigger, it’s then harder to do things. So it might help to stay on that trajectory. But I guess just thinking about this sort of as we all know when we exercise our muscles do get bigger so there’s always that possibility in physio and things so I suspect you know there is the chance for improvements especially when you’re on these treatments I would say. So with SMN plus anti-myostatin plus a really good physio regime, know, we might just get there. 

Portia 

Yeah, the combinations of really supporting the neuromuscular system and the body and the person as a whole is the way forward. 

So this pipeline that we have on SMA UK’s website, it doesn’t show us what’s in the preclinical stage.So is there anything else because we talked about the nerves, that’s the other, you’ve got your SMN, your muscles, nerves, and the other thing we could, is there anything happening in the lab at the moment? 

James 

So I’ll say we don’t tend to put them on here because oftentimes we either don’t know about them because they’re not yet published and sort of labs are working on things that we haven’t seen or because there’s often so many different labs working on so many different sort of preclinical potential therapeutics that it would be very difficult to sort of keep track of them. However, I do know that CURE SMA, for example, do keep track of some of the compounds that they’re funding and some of the treatment approaches that they are sort of backing. and I had a quick look and there are a couple that are neuroprotective that seem to have potential. 

For example, there’s one called P38aMAPK Inhibitor or an inhibitor. And so P38aMAPK is a protein found within different cells. And it’s also important particularly in the nervous system. And if you inhibit it in mice that have received SMN dependent treatments, it’s having a positive impact versus just the SMN dependent treatment  alone. 

Portia 

Yup. So that’s sort of one that I’d read about and heard and they have a couple of others on there that sort of seem that they could sort of ultimately lead to trials in the future if they continue to be successful and the evidence sort of supports their use. 

James 

That’s exciting. Yeah, I think so. Again, so, you know, I think there’s a lot of conditions that impact the peripheral nervous system, so the motor neurons, sensory neurons, and so there’ll be a lot of diseases and treatments that are not currently being tested in SMA that could be beneficial because there are many different genes, proteins, and processes that go on in the neuromuscular system that are likely to be impaired in SMA through loss of the SMN protein. 

Portia 

Yeah. 

James 

And so additional support of those pathways and processes and proteins are likely to be beneficial in SMA, as well as other conditions that are affecting those same cell types. So I suspect there’ll be lots of neuroprotective and muscle supportive options that over time will potentially be tested in SMA models and then potentially in trials. 

And I think probably we’ve said with all these treatments, it’s better the earlier they’re given.So in small babies, and there’s a lot, they even say neuroprotection, you’re protecting them for further damage. 

Portia 

Is there any possibility of sort of a rehabilitation rather than protection? 

James 

So I think that’s where the gaps are now, especially for adults living with SMA where treatments come later, to save them. 

Portia 

Is there any, do you think there’s any scope for regenerating lost neurons on lost muscles looking at that way. 

James 

Potentially, I think. I guess, sort of, on the negative side is that once you have lost a motor neuron fully from the spinal cord, and its axons are missing and it’s gone, you can’t then recover that. 

Portia 

Right.   

James 

But thinking positively, the peripheral nervous system has a much better capacity for regenerating than the central nervous system, your brain, the neurons in your brain. And so there are a lot of groups across the world who very specifically are interested in how motor neurons can regenerate and what happens when they’re damaged. So there’s a lot of research going into that there’s the possibility, I think, that if you have weakened motor neurons and weakened muscles that are still present, that they could be supported in additional ways in the future. I don’t know of anything specifically at the moment, but I think there’s definitely the capacity for that. 

Portia 

And it’s quite good I suppose, that it’s an issue that’s not just SMA specific. 

James 

Yes, yes, so there’ll be other people working on it. 

One thing that people have talked about in the past is using stem cells.  To sort of regenerate axons and nerves. There is some potential, but I would be very wary, I know in the past, in motor neurone disease and SMA potentially, sort of desperate people have been taken advantage of with certain treatment approaches perhaps. And I think sort of that regeneration element is really in its infancy. And the idea of using these stem cells is really something that is a long way off from being.  

Portia 

Yeah. I would say so. 

So talking about other conditions, I know that before we had the DM, the disease modifying therapies that we have now, people were prescribed salbutamol, which I think is an asthma pump drug. And they were saying that it increased SMN levels, which I was like, wow, that’s insane. Is that true? And is there any other drug, I think it’s called drug repurposing that we can think about for symptoms, I don’t know all the other things that come with SMA, such as fatigue and achy joints and all those sorts of things. 

James 

So let’s first talk about drug repurposing. 

 

That’s something that essentially means taking a drug that’s been approved for something else and then reusing it for a new purpose. So examples would be, I think…Aspirin has been used in the past for its initial sort of, I forget its initial purpose, but now it’s often used as bit of a blood thinner and sort of helps with potentially staving off sort of heart conditions and strokes. 

Another example is sildenafil, used to be used for hypertension, high blood pressure, and is now used for erectile dysfunction. 

So there’s sort of off-label sort of positive effects of drugs that weren’t initially sort of identified, but then can be reused for other things. 

Portia 

Okay. 

James 

With repurposing in SMA, I think it’s a little bit more targeted than that. It’s not just one drug having a completely different effect we didn’t know about. It’s more that there are drugs that are useful or potentially useful, for example, in a motor neuron disease or a disease that specifically affects the neuromuscular junction. So where the motor neurons connect to the muscle, there’s a lot of conditions that affect that sort of part of the nervous system. And those drugs could then also be then useful for SMA potentially. And kind of a cheaper way of doing it, I suppose, because they’ve already been through all those safety… 

That’s the major benefits of the repurposing process is that it’s a lot cheaper and faster and a lot of the different trials are not required to be able to progress more quickly. And that’s really helpful for rare conditions where speed is of the essence and actually already having information about these drugs is really helpful for the efficiency of the process. You also mentioned salbutamol.. 

Portia 

Oh yes, salbutamol yeah. 

James 

So it’s a compound that I think in models of SMA has shown to increase the levels of the SMN protein and have some value.When it comes to sort of patient clinical trials, I don’t believe that they’ve been done with salbutamol. So there is currently no real large quality controlled evidence from humans that it’s beneficial.I think there is some sort of smaller trials and sort of smaller anecdotes, maybe more anecdotal evidence indicating that it could be useful. But I mean, if you’re on any of the  SMN dependent approved drugs, the idea of taking salbutamol to enhance, I don’t think is something that is really required. 

But yeah, as to why it sort of increases SMN levels, I’m not so sure. 

There are quite a few other drugs that you might have heard of, so valproic acid and I forget the names of them, they’re not coming to me.But they are also sort of shown as a side effect. They increase SMN levels, but they’re likely doing a lot of other things as well. And it’s whether you want those other things to be occurring. And the answer is probably no a lot of the time…different drugs together and things like that to avoid contraindications. 

Portia 

That’s the word. 

So we talked a lot about drug treatments.I know that there are families trying, and adults I think as well, electrical muscle stimulation, where they have this machine that stims your muscles. And I’ve heard great things.And also on your swallow, I think people have been using it on a swallow. I’m just wondering from sort of the lab research, do you think there’s any value in that? 

James 

I like to think it makes sense. If you’re stimulating the muscles, you’re causing them to contract, it’s potentially simulating exercise and therefore could be useful. I know in some sort of conditions that are associated with inactivity and muscle wasting, for example, cancers, there’s some evidence that it could be useful. However, in SMA, I think the only real data that are out there are a small trial in I think early 2000s in Canada that had SMA type 2 and type 3 participants. And it was testing stimulation overnight at home for at least four hours or so, if not longer, on muscle in the shoulder and the bicep. And ultimately, it didn’t show any positive effects on strength, endurance, or any meaningful impact after six months. 

Now that’s not to say that in different types of SMA or, so this is pre-therapies, that actually with therapeutic support it couldn’t be useful. It could be that also different muscles might benefit from it. So I would say at the moment there’s no evidence to support it, but I think if people are anecdotally finding it useful, I think really…As long as there’s no harm, I can’t, I’m not a medic, I can’t say yes or no whether there’s harm occurring. I guess you would find that out individually if there was.But it’s something that, yeah, I think more research is required just really to either put that to bed and say no, it really isn’t working, or actually maybe there’s mild, mild benefit when combined with the different treatment approaches.  

What I would say though, I was having a look at this and there was a study this year in nature medicine looking at stimulation of the spinal cord actually. And they had these little devices that were sort of implanted into close to the spinal cord in the lower back region. And this was in people with SMA type 3 – sort of short periods of stimulation were shown during activity to really improve muscle function and endurance. 

And actually the really exciting part was that when they turned off these machines, the positive effect was prolonged and they actually felt it when the machine wasn’t on anymore. It was only three patients, and I think that’s not very many and sort of caution needs to be applied but it’s something again in the future that maybe larger trials will really show that it’s something that could really be helpful in addition to the SMN therapeutics, potentially in the more sort of the sort of type three forms of the condition. 

Portia 

Yeah, it’s exciting times, it really is, because we’ve got our three drugs and those pharmaceutical companies that made those first three, they’re still going.We’ve got the intrathecal, Zolgensma, we’ve got Biogen with their trying the higher dose nusinersen and salanersen coming through. And then we’ve got these combination therapies for looking at muscles and possibly nerve protection in the future. 

James 

It’s amazing, I mean sorry, since when I started my PhD it was 2009 to 12 and I worked on SMA in that period of time and just to sort look back on the landscape of SMA research and the clinical landscape, it’s so different to what it is now. It is amazing sort of the progress that’s happened. 

Portia 

Yeah, no, it’s fantastic really. Well, thank you for joining us. We’ll have to get you back to do another review of what’s coming up in a year.  

James 

Any time. 

Portia 

Thank you, James, so much. 

James 

Thank you for having me.