Chapters Transcript Video From gene therapy to focused ultrasound: Advancing the future of neurological care When I'm thinking myself about where we can take the precision medicine approach that has been so powerful in helping people with cancer. How we, how can we adapt that best into neurology? Um, for me, I'm just gonna say that the precision neurology, um, will like in the cancer world, um, take account of not only your genetic makeup, not only your biomarkers, not only your disease cause, but it's also gonna take into account your exposome. Hi, I'm Lindsay Carrillo, director of business development at UCI Health. Hi, I'm Doctor Sunilil Verma, Associate Chief Medical Officer for ambulatory and a laryngologist here at UCI Health. Welcome to Physician Huddle by UCI Health. Today we're joined by Doctor Claire Henchcliffe, the Stanley Van der Noort, professor and chair of neurology at UCI Health. Welcome, Doctor Henchcliffe. Thank you so much. Thanks for having me. That's a pleasure. So tell us a little bit about your background and How'd you get your start and how long have you been here at UCI Health? OK, um, you can tell from my accent, right? I'm not from here. So I grew up in the middle of England in the countryside and um I got the bug for thinking about how the brain works pretty early on. I was a pretty nerdy kid. Um, so it was absolutely thrilling to be able to go study biochemistry and then get into the lab at Oxford. Um, spent a brief time in Cambridge before coming over to um the US and never went back. Um, so I did things a little bit backwards. I did my research training before I did my medical training and it was while I was studying a little bit about development of the nervous system that I, again, I got bitten by a bug, um, the, the brain bug but this time neurology, so I went back to medical school. And I had um the enormous privilege of training with some of the greats that was back in in New York. um and they really inspired me to get into not just neurology but really to um dig down and and specialize more. So, for my uh clinical training and the rest of my career, in terms of patient care, Parkinson's disease has been my um my focus. um. I also, uh, as well as patient care, I love doing clinical trials. I love the research piece of it and of course, you know, we all want to nurture that next generation. So, working in movement disorders has been a really great field for me where I can combine that kind of academic take on medicine um with the um The challenges that patient care uh care brings. And, and how did we get you to come to UCI Health? Uh-huh. Um, so when I was back in New York, um, I worked at Weill Cornell Medical Center and in addition to kind of, I love building teams, um, I built up a team of movement disorders experts. But then I took on a larger role and became vice chair for research and realized I really, really like building teams and I think that's the challenge about being a chair. Um, UC Irvine. Has some things that make it absolutely unique. Um, it's a great medical center and I think here people really work well together. So there's that um collaborative aspect to the medical care, but we're sitting on a powerhouse campus. Right? And I think that was really what drew me in. Um, it's this opportunity to sit at the interface between um providing, you know, global level um really world class medical care but also thinking about well, We can still do better and how can we use the researchers, um, the engineers, the biological scientists, the public health folks on campus, how do we bring their approaches to um do something better for our patients? I have to say that about the Department of Neurology is that it's really connected to the research mission. It's very connected to the tremendous ecosystem that we have on campus, a lot more frankly than other departments. So that must have been pretty special to learn about walking and then also, I don't want to use the word exploit but really learn how to scale. Leverage. Yeah, and I, I think when I arrived, um, it was a smaller department at the time but boy, I was. I was so lucky to um come to a department where you've got some real world leaders in their subspecialties. And I'm thinking about people who um working very, very hard to treat um neurodegenerative disorders like amyotrophic lateral sclerosis, ALS, but also people who work in Alzheimer's, uh, people like me who work in in Parkinson's and um Some of the teams were already pretty mature and uh they got um fairly intense collaborations already going on. I'll also say that um you mentioned ecosystem, which is a really nice way of looking at what we do here and um In the Alzheimer's field in particular, we're incredibly lucky because we've got the clinicians in my department but then we've got the um ADRC with you know, a lot of NIH funded research, uh Alzheimer's Disease Research Center and um we've also got the uh in the Mind Institute uh run by Josh Grill and these people were already working um very collaboratively together. So we sort of had some models there, right? And then you think about, well, what more can we do in other areas. And yesterday, um, I had a really great conversation with our chief of clinical epilepsy and then the leader of the um epilepsy Research Center on campus and sparks were flying, ideas were flying. What does that mean for a patient who comes here? Like what's different about seeking neurological neurological care at UCI Health when they have all these res when, when you have on the background all these resources? Yeah, um, I'll say, uh, I'll give you a couple of examples. So, um, first of all, we're gonna provide that really world class care. We're really, um, hyper hype, my, my physicians are hyper dedicated in the department. I'm so proud of them. But then, I think in addition to the regular conversation that we have with patients about, look, here are your options, let's talk through them. We also can provide them with the option to get into something very new, um, something experimental. We run a lot of clinical trials. I believe we have over 100, um, open in the department. Um, and so when we talk to them about their care options, they've got the standard ones, but they may also talk about, for example, getting into a clinical trial of a gene therapy, getting into a clinical trial of a transplant therapy or getting into a clinical trial of um uh an antibody infusion therapy as well as all of the experimental small molecules that are out there. Wow. So just a lot of options, um, very focused and, and sort of literally, uh, state of the art if you will, or, or state of 2026 and what's coming beyond that then. Yeah, and I, I hope we can move, um beyond that. We've, we've put into place, uh, we have a lot of new faculty. We've been doing a lot of hiring and we've expanded. Um, and I think a lot of people who've come in really bring fresh ideas to the department and now we're starting to see. In addition to some of the older, older, more mature, um, multi-disciplinary clinics, for example, in ALS and Alzheimer's, but we're starting to see that approach come in in a lot of new areas. So, for example, we have a new headache program. Um, we joined the uh um we hired a neurogeneticist to come in and help us um develop eventually a more precision health type of approach to neurology. Um, and he came to us uh straight out of fellowship but was able to get us into a, um, nationwide network called the Undiagnosed Disease Network, which is NIH funded. So now we're able to take on people, um, I was talking before about treatment, but the diagnostics are really important, right? And there's a lot of progress that needs to be made there. So now we're able to take in people who've gone through the regular diagnostic workups at their own hospitals or with their own doctors, haven't successfully got a diagnosis, and then we're able to hook them into this nationwide system which has a lot of, um, you can imagine, pretty rich resources, right, for investigations. Can I ask you, the need for neurological care is so great and it Probably will just continue to grow. How do you think about that? You mentioned your hiring, which is so great and How do you, how are you going to approach trying to meet that need, or you know. Yeah, we, we know, um, Let me back up. Um, we know there's actually a shortage nationwide of neurologists, so we have to get creative. Um, I can keep hiring. We just signed on two more people this week that I'm absolutely, absolutely thrilled about. Um, but frankly, as we bring in our, our new faculty. Their practices fill up. So I, I think one of the ways that we can work um smarter is through more collaborations, more liaisons. Um, as you know, we have uh not only a new hospital on Irvine campus, we've staffed the new ambulatory care center. I have our neuro-oncologists working in their new cancer center. But then of course, we also now have 4 community hospitals to work with plus private practices who were starting to contract with and develop um closer relationships with. So I think there, there's a lot of nice ways that we can think about those collaborations. Through our relationships with these community physicians in the community hospitals, I think that we can get our expertise disseminated more easily. But also we don't want to take people out of their communities. So I, I think that that partnership there is um gonna be very rich. No, I, I love that because I think that's what makes UCI Health special. I mean, when you started, you started talking about collaboration and That's been a theme of what we've talked about, but it's not just collaborating with folks here on campus, it's collaborating with other physicians and recognizing, to use the word ecosystem again, right? It's an ecosystem of health that patients don't always want to be coming to the university, they want to be seen in their own areas and so it's about understanding which patients need to come here and which patients don't because it's just like you mentioned, you're growing, you know, in double digit percentages every year as a department. But the patients continue to fill up. Let, let me ask you this. How, what, how do we train more neurologists, right? At the end of the day, there just aren't enough neurologists, it seems, Doctor Henchcliffe, what is changing in medical education or what are the thoughts of what could change to get more neurologists to train? Well, we keep on lobbying to, um, we lobby at the local level. We love. Be at the national level. So, um, as we are, um, we have a fantastic training program here. Um, we have a residency program with 5 residents coming through per year. We also work very closely with uh CHAC, Radies CHOC, the Children's Hospital. So our folks get experience with them, they get experience with us. Um. In addition to um wanting to expand the residency program, we kind of have to make sure as we expand, that we've got the students coming in to fill it. So we, we love educating at all levels here. We've got a fantastic clerkship director who works very closely with our medical students. We've also had programs going out to um Local high schools or bringing the local high school students into us um to teach them that, you know, neuroscience is pretty cool. Oh boy, there's nothing better than trying to understand the brain and the nervous system. Um, and then kind of at the other end of the spectrum from the students. We do uh have a number of fellowships and we've been working really hard to um develop new fellowships. In fact, we just recently, we have a newish headache dedicated headache program and we just got approval to um kick off a head, a dedicated headache fellowship. Yeah. I mean, that's growth, right? Within a couple of years, you design that you've identified the clinical need for the specialty. You recruit, the patients follow, you recruit again, the patients follow and within a blink blink of an eye, you now have a fellowship program developed. I mean, that's really special. Yeah, well, we've got to fill it first, but um, but yeah, and I'm, I'm gonna give a lot of credit to um the new faculty who've come in who are hyper energetic and they just took this and ran with it. So in a lot of cases, it's uh, you know, I, I, I have done. Little else than just remove the barriers for them and um let them take this program and develop it in in in their, in their vision um with their, their view of what's important. I'll just say the same for the neurogenetics program and we've also kicked off, and I think this is gonna be something really cool for the future. We hired a neuroinformaticist, someone who is expert in machine learning and AI. Um, so we're now starting to set the stage for bringing in computer science, um, in a more actionable way. Of course, lots of research going on there, but we want it in the clinic, right? We, we want this to be helping our patients. We want it to help us, um, make faster, earlier, more accurate diagnosis and kind of um provide more data-driven therapeutic options. We touched on a little bit the growth at UCI Health. You know, we've acquired 4 hospitals in the last couple of years, just opened our new hospital at Irvine, set to open our 7th hospital, which will be a rehab hospital this year. And I know one of those very important elements across all these facilities is the stroke program, and you have a lot of amazing faculty in that area. Can you speak about that just a little bit, because the need, again, it's great. Thank you, thank you for bringing that up, um. Yeah, we're seeing more and more strokes, unfortunately. Um, fortunately, we also have, um, more therapeutics. Um, I'll just give a shout out to all of our collaborators because when I arrived, we, we have a comprehensive stroke center run by Doctor Yu and Yu, who's just Amazing and he also um is a mainstay of everything that happens for neurology in the hospital and to talk to him and a great fisherman as well. We we have had some leadership trips um. So, um, he is extremely well connected in the community, so we've also found that through him and through his team, that really helps us to um work effectively with the community physicians who are out there. Um, I'll just say, you know, it's not only the The clinical care that we can provide as neurologists, but he's developed such strong ties with um PMNR, the, the rehab docs, but also neurosurgery. So neurointerventional radiology, which is um an amazingly powerful set of techniques, um, sits within neurosurgery and those um attendings just really work hand in glove with uh, with our, our folks. Um. We've got great nursing, uh, we've got great social workers, so we really have like this incredible complete team. Um, they're kind of triple threats, I think these people because they, they, in addition to the um clinical, they're doing research, they're doing clinical trials and they're also fantastic teachers. Um, and I just want to give a shout out to uh some of the community docs because I, I've just signed off, for example, on one of our new community, newly affiliated community neurologists who is leading an NIH um funded clinical trial. Um, they're also involved in teaching. So you can see this is, this is pretty high level network. What's it like building a team? I mean, you certainly didn't start off small and it's a, and it's a, so you started off big and then now it's a very large department. How do you balance all of that? I don't. You can make you feel better. Um, yeah, I think when I, when I came here, we were, um, probably almost 40 attendees and we're we're way over 60 now. We've got another 15 spots open so we're still, uh, still hiring, apply today. Absolutely. Um, I've got fantastic leadership in the department. Um, I've got an executive committee comprised of several vice chairs, so I have someone um who's in charge of uh Mark Mapstone is vice chair for research. I have Lisa Flanagan who is just incredible as vice chair for academic personnel, but she's also an outstanding laboratory researcher working on kind of leading edge um stem cell science. Um, I mentioned Doctor Yu already. He takes care of our, our inpatient affairs. Gabby Tight takes care of the ambulatory affairs and uh Sarah Stone Nezza. Who is an incredible educator with a national presence. Um, she's our vice chair for education. And then under them, we have another level. We've got the divisions, we have the division chiefs. Um, and as I mentioned, some of our, our new faculty are just incredibly energetic and uh I don't have to, I just need to remove the barriers. That's really fun to to create a to be able to do that, to have a system where you just let people do what they want to do. And you pick, yeah, what they wanna do with their best at, you know, work at the top of their life, but that means you pick the right people, you know, if, if you can, if you say it's just about removing the barriers, you've picked the right people and you. Sort of filtered out what their desires are and now you just, you just water that plant and let it grow. Um, I love the way you said that and actually I was thinking about as, as we were talking about my background and what brought me here, um, one of the things that I love to do and I think the most rewarding part about leading the department is actually cultivating the people in it. It's the, it's the mentorship piece and you know, I said I, I love growing things and that goes from plants or Whatsoever. I love, I love building things. Um, and I think the chance, you know, to put, um, bring in people, expand the teams, give some guidance, provide them with these, we, we have incredible resources here at UC Irvine, right? So we're pretty lucky to work with people like you two, and people in the hospital who are gonna help us to understand. Some strategy about our future growth and where some of the exciting things are um and support us with those exciting things. So, it's been, you know, growth of personnel, and you mentioned growth of the space that we have to work in. But it's also growth in terms of other resources and I'll just say in the new hospital, for example, um, we um are kicking off a completely new program for us. We've always had fantastic functional neurosurgery. It's very sophisticated. Um, but now we have a new gadget, um, to play with. It's magnetic resonance, uh, guided focused ultrasound. So it allows us to do non-incisional surgeries, which the idea of that just blows my mind, to be completely honest. When I heard about it in a, uh, I think it must have been one of the meetings we held or we that you hold and I, I have the opportunity to listen in. I immediately started Googling on the side because I just didn't understand what this could be like. Like it just, it seems like fantastical. It, it is and you know, I've I've seen cases um as we've been kind of training ourselves to um understand the power of this technology, which is, you know, it's like using multiple um beams of ultrasound, high intensity that then combine in one little laser focused place and they're going to um Make a tiny little very precise lesion in the brain. So as we were training and trying to understand how this um works and what it means for the patients, I had the privilege of sitting in at a different institution and um watching people's tremors just poof um go away a single session and this is outpatient, right? There's no overnight stay, there's uh no um spending a half a day in the recovery room and and then waiting to go home until the next day. Um, I think the exciting thing about that is in the the foresight of our leadership in kind of helping us, um, get that gadget. Um, it's, it's really interesting because what you can do with it now is the non-incisional surgery. What we can do in the future is really amazing. So, um, you know, the research piece of this is to break down blood-brain barrier in selected areas. It helps you get your biologics through it. Means you can start thinking about um rather than neurosurgical delivery of a gene therapy, you can start thinking about putting it into the bloodstream and having it delivered through the broken down blood-brain barrier. Um, it's also possible. Uh, to use devices like this for neuromodulation. So instead of making a lesion, you can just kind of damp down activity in a particular place. So you can tell I'm a frustrated neurosurgeon, right? Or a James Bond villain, I think. Yeah, the medulla oblongata. A lot of lasers. Um, that's incredible. Um, you've mentioned, you know, uh, stem cell transplants and new technology and new innovations, and I know that that's a specific passion for you and your work specifically. Tell us about some of the exciting things you're doing in that arena. OK, um. So I got really interested in um sounds like science fiction, but I got really interested in the potential for regenerating, regrowing, repairing the brain um way back when I was in fellowship and my mentor at the time, Stan Farn was a real pioneer in the field and they had been looking at using um tissue, not, not stem cell um derived because that technology didn't exist at the time. Um, but they were using a tissue transplant to try to repair the brain in Parkinson's disease. Um, it didn't, none of those programs flew. Um, it's really too many limitations with the tissues and cells that they were using. But when you combine the sort of surgical approaches and that concept with the new advances in stem cell medicine that let you grow stem cells pretty well infinitely, right, an infinite number in the lab. And you can then coax them to become what you want them to be. So you could turn them into heart muscle cells or you can turn them into my favorite, the dopamine nerve cells, which are the ones lost in Parkinson's. So we were interested in that a long time ago. It wasn't until I got to um Weill Cornell and started working with some scientists at Rockefeller and Memorial Sloan Kettering Cancer Center um that we, we said, well, look, you know, that the science is, is, we think it's there and it's time for another go. Um, we spent some years, uh, with the, the lab team were incredible. They spent so much time, um, and expertise on really making sure that these cells were, um, safe, um. Um, really rigorous quality control and thinking about how we do the surgery. So it was, I think, 2020 that we did the first surgery. By that point, we already had experience at our place of doing one surgery with a different, uh, a different institution in collaboration with Mass General actually. Um, but we started the surgeries on people with quite advanced Parkinson's. Advanced to the point where they're still doing quite well, but the medicine, the conventional medicine wasn't holding them through the day. Um, so this really involves a single surgical session, um, where using stereotactic guidance, you're gonna deliver the cells that you've developed in the lab to very precise targets within the brain. And then what we believed would happen based on all of the preclinical work was that these cells would survive and they would start talking to the host cells, right? Um, in fact, Several years later and with 12 pioneering patients who went into this, first in human, it had never been done before. Um, so that was uh very, very brave. Um, and we've now followed those people and we understand from the brain scans that um the cells have survived. The main aim of this initially was to um look at the safety and tolerability but of course you want to learn about what the cells can do. And so we've actually seen some improvement in some of those people. I don't want to make too much of it because, you know, in a rigorous clinical trial um that would prove efficacy, you're gonna be having a sham control. You're, you're gonna have a placebo arm and we didn't do that which is appropriate in the first in human trial. Um, but there's a lot of encouragement there and we actually now are just opening up, um, the subsequent clinical trial, which is a placebo controlled or sham surgery controlled and that has gone, that clinical trial program has gone from um 3 center, which was UC Irvine, uh, New York and Toronto. Now it's at multiple centers across the country. So it's really exciting to see that happen. Wow, that's incredible. Um, we've talked before about, um, research. You, you do a lot in your space. Where are the more exciting, uh, things happening elsewhere in your department that you are just so thrilled about? Absolutely. Um, it's hard to know where to start. Um, we've got, um, People who are, we have a lot of NIH funding in our department. Um, we've got people who on the one hand, are looking at care delivery and caregiver burden in in various communities right through to the other extreme where we've had um one of my faculty who was working on developing a brain machine interface and he is now trying to understand, he's gone one step further than that. And he's now trying to understand how you can put neural networks together in the laboratory, sort of on a chip if you like, and help them learn, help kind of direct them in how they talk to each other. Um, we've got people who are, um, pursuing gene therapy, um, and I'll just say that that now has come to fruition in one area which is, um, neuromuscular, um, there's a neuromuscular disease affecting kids where there is an approved gene therapy. So it's really great as you're getting into these experimental therapies to understand that experimental therapies in the past that you have worked on have actually kind of come through and they're being delivered to um to patients now. Um, I'll just say there's a lot of research ongoing with our collaborators on campus. So, um, in conjunction with engineering, bioengineering, for example, and looking at devices that are better going to help, gonna help us better understand epilepsy and better treat epilepsy. Um, I mentioned that we have uh stroke trials going on and um Um, one of the biggest programs that I should mention is centered around, um, dementia. So I mentioned, um, we have worked, we have a really great network of people in my department and in other departments who are working on Alzheimer's. But actually, not that long ago, several years ago, it was discovered that there's a different type of dementia and people have been getting clinically diagnosed with Alzheimer's. It's a completely different pathology. It's called LA and um one of our, our, our faculty, our um chief of the division of memory disorders, Doctor Sajadi is um newly NIH funded um to start working on that. And it's a really lovely collaboration that he's got set up because he'll lead from UC Irvine, but there are other UC centers and there are other centers along the west coast who are going to be participating in this. So this is um just a a small number of the um uh programs that we've got running right now and I think the the last thing is, as I, as I mentioned, um, we strongly believe that computer science is going to help us in our mission to provide better care. And so there's a lot of neuroinformatics research going on there. Um, that's been really interesting because it gives you the chance to get into a field called predictive analytics where you can take, you know, maybe eventually, a digital twin of your patient and um take this, you know, big data from them and start using that data to predict which Medication are you going to do with when you get enough data, yeah, yeah. Are you someone I should send to the neurosurgeon earlier rather than later, or are you someone who will never need a neurosurgeon and you can take these medications. Thank you very much. Yeah, the power of big data and being able to analyze it, right, and personalize it is certainly something of the future that when we were in training was, uh, again, fiction. And reality now. Yeah, and I, I think, you know, I, um I love the art of medicine and that's how we personalize right now. So, I guess when I'm thinking myself about where we can take the precision medicine approach that has been so powerful in helping people with cancer. How we, how can we adapt that best into neurology? Um, for me, I'm just gonna say that the precision neurology, um, will like in the cancer world, um, take account of not only your genetic makeup, not only your biomarkers, not only your disease cause, but it's also gonna take into account your quote exposome, the environment that you're in, what you get exposed to, but as well as that, then we have to think about, well, what's the social interaction? What's the social familiar like? So, I think that all of these things that we have incorporated into the art of medicine in the past are gonna be, they are not going to be dropped at the expense of biomarkers, but I, I think that we can weave all that data and um so I'm, I'm very excited that we've got our, our neuroinformatics piece in place and I really, I do want to see that grow. Nicole, Doctor Hinchcliffe, I could talk to you all day. I have a million questions, but probably need to let you get back to your important work. So we just want to say thank you so much for joining us today. Thanks for having me. Um, it was really a real pleasure to be able to spend some time with you. Thank you. This has been Physician Huddle by UCI Health. Thank you for joining us. This was an episode of the Physician Huddle podcast by UCI Health, produced by Brett Shaheehan, Angelica Yugubi, and Victor Ting. 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