Hot Topic: Focused Ultrasound in Movement Disorders - Blood-Brain Barrier Opening

[00:00:35] Dr. Nir Lipsman: My pleasure. Hello, Michele.

[00:00:36] Dr. Michele Matarazzo: So can you start by explaining what the blood brain barrier is? Well, let's call it BBB, that's shorter. And so what the BBB is and its role in the normal brain.

[00:00:47] Dr. Nir Lipsman: Sure. So the BBB is critical component of the neurophysiology of the brain. It's a semi permeable barrier comprised of different cellular structures, including endothelial cells and [00:01:00] others that very tightly regulates what can and can't access the brain parenchyma. It's essentially an invisible to the naked eye barrier that is comprised of those cells as well as very tight connections between them that imposes a chemical as well as a physical limit on what can gain access to the brain.

And typically large molecules can't get into the brain and smaller molecules like glucose, oxygen, and others can get into the brain. It's very tightly regulated and serves a critical function to protect the brain, but also imposes a major challenge for the delivery of potential therapeutics to the brain as well.

[00:01:40] Dr. Michele Matarazzo: Yeah, that goes in line with my next question. So all of the things you were saying sound like a very important function. So why should there be a need to open the BBB?

[00:01:50] Dr. Nir Lipsman: So this arose from the recognition that much of the development of therapeutics, certainly in the world of pharmaceuticals [00:02:00] lead to the development of very large compounds, compounds that maybe preclinically in animal models show a lot of promise in their ability to treat. To gain access to brain pathology, but it was quickly discovered that very large molecules can't get into the brain.

So, there exists a kind of gap in the academic world where very promising therapeutics are developed. But again, the blood brain barrier essentially excludes almost 100 percent of large molecule therapeutics from gaining access to the brain. So, it's a major barrier, for lack of a better word, for our ability to get therapeutics.

There's no question, of course, that it is a critical, important structure for the health of the brain and keeps a lot of toxins and large molecules and other in other compounds, both endogenous and oxygenous from gaining access to the brain. But it also prevents potentially promising therapeutics from getting access.

And this applies to many different kinds of conditions, whether it's oncologic or [00:03:00] whether it's neurodegenerative or other kinds of conditions.

[00:03:03] Dr. Michele Matarazzo: Great. Now, how does the focused ultrasound work to open the BBB? How is the process? How does it normally work?

[00:03:10] Dr. Nir Lipsman: Yeah, so it's an interesting story how it was developed. So currently when we talk about focused ultrasound in the brain we can break it down into different mechanisms, the different ways that ultrasound can interact with brain tissue. So oftentimes the most frequently familiar use and mechanism of ultrasound is called high frequency ultrasound, and that uses high amplitude, high power, ultrasound energy, acoustic energy to generate very discrete lesions in the brain with thermo coagulative necrosis. So basically burning a hole, very precise hole in the brain. And that's used for treatment of things like tremor. And I'm sure that others will discuss that as well. So we're not talking about that use of ultrasound.

We're talking about something called LOFU, low frequency ultrasound. So with low [00:04:00] frequency ultrasound, the device looks very similar, but the main difference is the power and the frequencies used of the ultrasound are much, much lower. So we know that ultrasound itself, low frequency ultrasound itself, cannot open the blood brain barrier.

We need a mechanism by which ultrasound can interact and that's where microbubbles come in. So what we do with microbubbles, we use a contrast agent that contains microscopic air filled bubbles and that we inject that i mmediately prior to the procedure. Those microbubbles will circulate throughout the body and get to the brain.

And once they're in the brain we expose the region of the brain that we want to open the BBB to ultrasound. Those microbubbles will then absorb the energy, the acoustic energy, and they will oscillate very, very quickly, upwards of half a million times per second. And they will cause a physical, mechanical disruption of those cells that comprise the blood brain barrier, pulling apart [00:05:00] the connections between the cells.

And creating a kind of window, a temporary window that we know lasts for only a few hours and that permits whatever is co circulating in the bloodstream access in much larger concentrations to the regions of the brain that we've exposed to ultrasound. So it's a kind of opening up of a window that is mechanical, that is a result of energy being absorbed by those microbubbles.

[00:05:23] Dr. Michele Matarazzo: Well, you made it sound like a very clean method, but would you say that, is it that safe? I mean, you explained the example of a high intensity focused ultrasound where you make lesions in the brain, like you said, ablation for thalamotomy and so on. But isn't that a concern also that you can have some effects on the brain tissues apart from this temporary BBB disruption?

[00:05:45] Dr. Nir Lipsman: Absolutely. I mean, we're sort of witnessing and we're living through and working through the development of a technology and kind of real time. So prospectively we are studying not only, the efficacy or does it work, but does it [00:06:00] achieve what we want to achieve, but we're also obviously clearly first interested in, does it work number one and is it safe.

So, to my mind, Focus Ultrasound, at least BBB Opening, is one of the most studied devices and techniques out there from a preclinical animal model perspective. And when we looked at this, we reviewed hundreds and hundreds of animal models. Animal models that range from very small animals all the way up to larger animals, etc.

And the safety profile was quite favorable when one looked not only at sort of one can look at safety microscopically and one can look at safety behaviorally as well. So on a microscopic level, it looked like the technical parameters were optimized such that the blood brain barrier can be opened with no associated bleeding.

But of course, it all depends on the technical parameters that you use and translating that to human populations. So when we started doing this and the first indications that we started investigating BBB opening was in [00:07:00] brain cancer. actually in glioblastoma. And in those patients, you know, the tissue was radiated, the tissue was previously operated.

And in fact, we found that we can safely open the blood brain barrier and do so reversibly. And every time you trial or you investigate BBB opening with FUS in a new population, the safety profile really needs to be refreshed because of course you're using different tissue. So in Alzheimer's disease, we are targeting regions of the brain that are amyloid positive.

And of course, amyloid can render. The blood vessel is very fragile and prone to bleeding. In Parkinson's disease, we're targeting deeper areas of the brain in the basal ganglia and the putamen and striatum. And those are deeper, very, very vascularized regions of the brain. So in all of these different indications, the safety questions begin anew.

And that's why we conduct the phase zero and phase one trials to better characterize the safety profile. Certainly compared to HIFU, the safety profile is different and because it differs in fundamental ways. [00:08:00] With LOFU, we use much lower powers than we use for HIFU. So we don't see an appreciable temperature rise, actually, when we use low frequency ultrasound as opposed to using high energy, high temperature rises with HIFU, so you don't see a lot of the thermal consequences maybe of a lesion that is made too large or too close to critical regions. So the safety profile will certainly differ and something we're actively interested in measuring.

[00:08:27] Dr. Michele Matarazzo: Great. Now, well, you explained that the idea of opening the BBB to get molecules into the brain is not something very new while this technique is more novel. There other techniques to open the BBB or is this just the first one and if there are, how does this compare to other ones?

[00:08:45] Dr. Nir Lipsman: It's a great question. And in fact. Of course, we've known about the blood brain barrier for decades. We know that it imposes this limit on the brain. It's an immune, what we call the brain is an immune privileged organ. We know that because of the blood brain barrier that it prevents things from gaining access.

And [00:09:00] we know that it's been a challenge to pharmaceuticals and others for many years. So people have tried different strategies, of course. One strategy, for example, was diuretics. So, mannitol, for example, is a diuretic agent used very commonly in the neurosurgical world and leads to a shrinking of those endothelial cells that make up the BBB.

And people have tried to co administer mannitol with other therapeutics, unfortunately not found to be very effective and associated with some side effects as well. People have tried more direct, what we call direct cranial approaches, so they try to open the head and maybe during an operation for something like a brain tumor, they insert wafers that are filled or impregnated with different chemicals or different compounds as a direct means of accessing brain pathology to overcome that barrier.

People have tried something called convection enhanced delivery, which are catheters that are inserted directly into the brain. And through what we call bulk flows, a large volume flow, we try to overcome, basically overwhelm the blood brain [00:10:00] barrier to get things delivered in. So all of these strategies are very much of interest but unfortunately have met with either very limited efficacy so they don't work.

Or they could be very expensive, especially if you try to, for example, re engineer a compound to fool or trick the blood brain barrier in order to overcome it. Or there are too many side effects. So the main difference here with focused ultrasound is that again, the wealth of preclinical animal data suggests that this is safe, it's temporary.

So the blood brain barrier closes up again afterwards. It's also done under image guidance. So all the procedures are done in the MRI. So We can prescribe specific sequences in order to check for the things we worry about like bleeding and swelling, etc. And patients are of course awake during the procedure and we could test them.

So a lot of the risk is mitigated by some of these, by some of these maneuvers and features and I think that the precision of it and the fact that you can effectively target virtually any brain region makes this an attractive [00:11:00] alternative.

[00:11:00] Dr. Michele Matarazzo: Great. Well, thank you very much for all this background. Now let's dive into what we know about BBB opening in movement disorders in neurodegeneration. What evidence do we have right now and specifically how can we target in some ways neurodegeneration or other kind of movement disorders using BBB opening? 

[00:11:20] Dr. Nir Lipsman: That's a good question. I mean, it's something that we're actively interested in. I would say, and I would profess right off the bat that there are many more unknowns than knowns right now in the field. Several years ago, we convened some of the key opinion leaders in the area at a meeting and sort of the goal was really to figure out even a list of potential questions for the field, let alone coming up with answers.

And there are many, many questions. And they include which kinds of populations should you target and at what stage of their disease? Where in the brain should you open the blood brain barrier? Should it be cortical, subcortical, which elements of the basal ganglia? And critically what should you deliver?

So let's say you can [00:12:00] open the blood brain barrier. What is the most promising therapeutic? If you could list any, what would it be? Is it going to be an antibody? Is it going to be some kind of enzyme replacement therapy? An anti inflammatory agent, some genes in the future, gene therapy down the road.

So all of these are burning questions, I would say, in the field. And I would love to say that we have definitive answers to all of these, or some of these even, but we don't. But I think it's critical that the field grow in a kind of iterative fashion. That one of the critical questions we have to establish first is, can we do this?

Can we open the blood brain barrier safely? Can we, from a technical perspective, achieve opening and closure? Do patients tolerate the procedure well? So these are critical questions that we have to ask first while in parallel we develop therapeutics or develop answers to those additional questions.

 So I think we're at an exciting part of the development of this field where there are more questions than answers, but I think that's why many of us are intrigued by this area.

[00:12:59] Dr. Michele Matarazzo: [00:13:00] Great. And actually, well, you and other groups have already published some data, right? in some Movement Disorders, specifically in Parkinson's disease,

[00:13:06] Dr. Nir Lipsman: That's right. So this work can't exist in a vacuum, of course, it's highly multidisciplinary and I'm very privileged to work here in Toronto with the Movement Disorder Team at Toronto Western Hospital specifically Dr. Kalia, Lorraine Kalia, she's our Neurology Principal Investigator and Dr. Sunil Kalia, who's another functional neurosurgeon like myself, and we developed a trial where the goal was to open the blood-brain barrier in the putamen in patients who harbor a genetic mutation for Parkinson's in their GBA genes. So this is a sub form of Parkinson's disease where patients are deficient for GCase Glucocerebrosidase.

And there is compelling preclinical data and clinical data, but preclinical data predominantly that supplementing patients with GBA PD and those who are homozygous for the mutation. Those with Gaucher's disease, Parkinson's disease may benefit from supplementation and from enhanced delivery of [00:14:00] GCase and Glucocerebrosidase.

So this is a enzyme replacement therapy that is already approved. It's Health Canada approved, so we can use it off label. And we can use this as an opportunity to try to answer those very questions. I alluded to which is can we open the blood brain barrier? Can we safely do this from a technical perspective?

And can we enhance the delivery of a potentially promising therapeutic? So we did develop this trial was a phase one trial and we published it a year or two ago in Movement Disorders and we did find that we can safely open unilaterally the blood brain barrier open in patients with GBA PD while we co deliver GCase serozyme in this case and use that data to develop the current trial that we're doing, which is a larger phase one, two trial in a larger number of patients. So we do have this promising experience that suggests that from a technical and safety perspective, we can proceed.

[00:14:52] Dr. Michele Matarazzo: Amazing. Now you have published this very important article, but other very interesting studies. [00:15:00] And well, you are one of the most experienced researchers in the field. Now, what do you think are the main challenges and limitation that we will have to face in the future?

And just to mention a couple of them, that comes to my mind. For example, we opened the BBB, I guess even opening it, there is a limit in the size of the molecule that we can deliver, right? We cannot just deliver anything. And also something else that comes to my mind. If you would like to comment on this. Neurodegenerative disorders are usually widespread disorders. Now, how good is to have a focal technique? Isn't it better to kind of target the entire brain or could we potentially apply this to the entire brain, for example?

[00:15:42] Dr. Nir Lipsman: Great questions, and I just wanted to highlight that your group and the group in Madrid led by Professor Obeso also sort of pioneering this technique and has published work in PD dementia and really exciting work preclinically and clinically in the BBB opening. And one of the fringe benefits I [00:16:00] think of when working in this field is that the community right now is small, but growing for sure. And how terrific it is to share ideas and to communicate and collaborate with other centers like your group and other groups around the world and sort of share these kinds of ideas.

 So certainly an exciting element of this field.

[00:16:17] Dr. Michele Matarazzo: Of course, I agree with all of this. 

[00:16:19] Dr. Nir Lipsman: So your question is a correct one. And one, we often think about, so for sure, focused ultrasound is often touted as an incredibly precise. An atomic temporal and spatial precision that we can achieve with focus ultrasound.

So what good is that for global diseases, like Alzheimer's disease, Parkinson's disease, where you can have multiple neurotransmitter deficits in multiple brain regions. And the point is true and well taken. 

So a few things, I think are critical. Number 1, we are treating much larger volumes now than we were several years ago. So I think the volume limitations will decrease. And we saw recently published work, for example, in the U. S. in Alzheimer's disease targeting significant volumes in the frontal lobe that we weren't treating even a [00:17:00] few years ago. So, so yes, we will be able to treat larger volumes. Second is we know that in diseases like Parkinson's that abnormal protein deposits, Tau and others, they do accumulate in sort of fairly predictable ways, especially in early stages of the disease.

So targeting early enough, we may be able to target critical nodes of the development of these diseases to try to prevent and slow things down. And ultimately, I think where the field is headed is likely the delivery of disease modifying treatments, whether it's gene therapy or others. And there, I think you can certainly target fairly focal regions of the brain, dopamine producing areas, cholinergic areas, and other diseases where perhaps you're providing the brain with the machinery it needs in order to manufacture the compounds that it needs in order to have an impact.

So I do see this as a field that is evolving in real time. So the procedure now is very different than it was a couple of years ago and I anticipate that in a few years it will be very different [00:18:00] as well. And a lot of these limitations that we're seeing now, whether it's size or volume will be eliminated eventually.

[00:18:06] Dr. Michele Matarazzo: Great. Well Thank you very much for all this information. And thank you for sharing all this knowledge you have acquired during these last few years. Can you finally share some of your future research plans and how they might influence the field?

[00:18:23] Dr. Nir Lipsman: Of course, yeah, no. And again, it's my pleasure to join. I mean, I think that the future is bright in the field of focus ultrasound. What we're very interested in is better characterizing the response that we're seeing with blood brain barrier opening so that we can really optimize from a technical and clinical perspective, the procedure, making sure that we're opening the blood brain barrier for small amount of time and that we optimize it for the delivery of whatever compound we want to deliver.

We're interested in expanding our indications. We have several trials looking at the oncologic space, including in pediatric oncology and brainstem tumors and children, and we're interested in working with [00:19:00] our pharma partners to try to improve the delivery of promising therapeutics that perhaps did not work in other trials.

We also know that the blood brain barrier is a kind of bi directional road that not only does it prevent things from getting in, but getting out as well. And focus ultrasound may one day be used as a potential liquid biopsy strategy to help liberate biomarkers for important brain diseases, Parkinson's and Alzheimer's, so that we can either monitor or make a diagnosis non invasively in a more objective fashion, so.

All of these things are on the table, whether it's imaging, whether it's technical, whether it's clinical. I think the future is bright for the field for sure.

[00:19:37] Dr. Michele Matarazzo: Well, thank you again . We have discussed the focused ultrasound mediated BBB opening and its potential applications in movement disorders with Dr. Nir Lipsman from the University of Toronto. Thank you, Nir, for your insights and contributions, and thank you all for listening [00:20:00]