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EP on EP Episode 75: CPVT--Gene alteration therapy ...
EP on EP Episode 75: CPVT--Gene alteration therapy ...
EP on EP Episode 75: CPVT--Gene alteration therapy with Silvia G Priori, MD, PhD
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Video Transcription
Hi, this is Eric Vrstovsky and welcome to another segment of EP on EP. This is a very special segment to me for multiple reasons, not the least of which is the topic, but more importantly is the person. We're going to have the privilege of listening to Professor Sylvia Priori today to discuss a very exciting area of ongoing research she has in CPVT and how it's morphed into therapy with gene alteration. Syl is the professor of cardiology at the University of Pavia in Italy and Syl, thank you all the way from Italy to do this. I can't thank you enough for giving us the time. Thank you very much for having me here today and I'm very excited to be interviewed by you. Well, I hope you'll keep that way. So listen, this is, I have had a peek into your work and the others haven't, so I'm going to take you from the beginning if you don't mind. You can build the case. Let's talk about CPVT as a problem. Can you explain to the listening audience what is CPVT and its clinical manifestations? Yeah, CPVT is actually catecholaminergic polymorphic ventricular tachycardia and is a disease that was described by Philip Kummel in the 70s. Philip described this disease that was leading to sudden death young adolescents and children and described the specific arrhythmia that is the distinguishing hallmark of CPVT that is a bidirectional VT. And you and I and the gray hair among the audience, you know, we remember that bidirectional VT is actually seen in digital toxicity. So that concept, you know, really led us to start thinking that the mechanism could be, as it is the mechanism in digital toxicity, triggered activity mediated by delayed after depolarization. On that concept then we started considering that the problem, the culprit gene for this disease would be regulator of calcium. And then when the Finnish group identified that the gene would be in a certain area applying linkage analysis, we noticed that in that area there was the cardiac rionidine receptor that is the key controller of calcium inside the cardiac cells. So in 2001, we discovered the gene and from there, you know, we were able to identify more patients, the community started being very inactive genotyping individuals, and now we know that these conditions is not so rare. There are other genes that cause recessive forms of CPVT, meaning that you need to have a copy of the abnormal gene from the mother and a copy from the father. Usually it happens in consanguineous family. So the patients have symptoms that are very similar to long QT syndrome, except the QT is normal. So they have a syncope during stress or emotion, but the difference that is a big advantage for the clinician between long QT and CPVT is that while in long QT you have patients having the syncope, but you can never in the clinic induce the arrhythmias on a provocative test, with CPVT we can put these patients on the treadmill, exercise them, and observe in the vast majority of them the presence of arrhythmias, either bidirectional or polymorphic VT. From the fact that the disease is associated with sympathetic nervous system activation, the fundamental therapy is based on beta blockers. More recently, actually about 10 years ago, so not very soon. Recently is a relative term. Yeah, exactly, it's a relative term, but Nolman described that flecainide could also be an add-on therapy on top of beta blockers, and with flecainide we've made some advancement in the understanding on how to treat these patients. Left cardiac sympathetic denervation might be another option, and of course the defibrillator is another option, not very much friendly to our patients when they are children or adolescents, though. And so, you know, we have different options for treating the patients. The problem remains that when these patients drop the therapy, forget to take it, they are exposed to risk. So I think that it's still a disease that is a challenge for the clinician. We have approximately a 25 percent of patients that, despite full dose of beta blockers, have a recurrence of an arrhythmic event on nadolone. Interestingly, you might be familiar with this concept that again was a proposal of Philippe Kummel. The patients respond much better to nadolone than to any other beta blocker, so there is also the challenge that nadolone is not available in several countries. Tell us about the pioneering work you're doing in gene therapy for this problem. Yeah, we started actually 11 years ago to work on gene therapy. It takes a lot of time, but it's fun, so we don't realize that it's so long that we have been starting with that. The concept being that for these channelopathies, the patients still suffer of death when there is a drug that works because very often they forget to take one, two, or three tablets, or when they are adolescent, they say, yes, I'm taking the medications, and it's not true because they don't want to take the medications. So we started thinking about something more permanent, more radical, that is how to correct the substrate by delivering nucleic acids. So if you have, for example, the loss of a protein, you can think of a therapy that puts the DNA for putting back the ability of the cells to produce the protein that is missing because of the mutation. Then on the other side, if you have a mutation that is a gain of function, too much work on the side of the protein, then you can turn it down, putting RNA in the cells and using RNA interference approach to turn it down. So, you know, it's like driving a car. You accelerate or you use the brake, and you can develop these therapies. So after we demonstrated the efficacy of this therapy in mice models for recessive and dominant CPVT, other investigators have started proposing other ways of doing gene therapy, suppressing, increasing other protein, and right now in CPVT, where we have a very good animal model in the mice with genetic mutations that are present in patients, we have a very nice spectrum of different approaches that could be used for patients. We have had a trial approved by FDA for the treatment of recessive CPVT, so this is something that at least has had the step of being approved by regulatory. So, as you know, it takes a lot of time to take these things to the clinic, but we are working now with investors and biotechs to try to optimize vectors, promoters, you know, there is not just the gene, the DNA or the RNA that you put in, but there is also how to make it selected that is not expressed in other tissues. So right now the work is really in the optimization phase so that we can go to a clinical trial in under the best scenario. As you know, gene therapy has been tried in four trials for heart failure, all testing the same therapy to control intracellular calcium in heart failure, and it didn't work probably not because of the strategy, but because of the quality of the gene product. So also in that respect, there is now a lot of efforts on the side of pharma and biotechs to provide new tools for the optimization of the delivery of these gene therapies. This is exciting stuff, pretty heady stuff. Let me go back just a moment, because I know I had the advantage of you speaking at Graham Rouse at our institution a couple of years back on this very topic, and you showed some preliminary work, not in humans, but in other models where it seemed to work, right? I mean, it isn't just a concept. Haven't you done some actual testing in non-human models? Oh yeah, in human models we have tested in mice, and now with the funding of the European Union, we are developing instead of genetically modified mice, genetically modified pigs, so that we will be able to test the gene therapy in hearts that have the same signs than the humans, and for us this is the ultimate step before going to humans, because even if, you know, the study has been approved, we think that it would be very important to be able to demonstrate that we can have a safe delivery, uniform distribution throughout the heart before going to humans. So, as you look forward, I mean, I know where you are now, you're sort of on the precipice of getting into human studies. Give us a timeline. I mean, you know, for years we've heard this premise about there's going to be gene therapy for all these diseases, and as I get older and older, I'm really hoping you come out with gene therapy that's going to do something for everything that I might get. So, where do we stand? I mean, if everything went the way you would hope, when do you think you would actually have something for the clinician to use? Yeah, I think that the pandemic has impacted this thing in the sense that we are all getting these vaccines that are delivering in our bodies RNA, and therefore, I think that even in the mind of people, this is facilitating the time in which we will be ready to say, also for the heart, we will deliver gene therapy. As a matter of fact, if you look at other areas of medicine, for example, for thalassemia, for hemophilia, for many conditions, liver diseases, you know, the field has gone very, very fast, and I think that we could really consider that the hemophilia could be defeated, you know, a disease very complicated to treat with a lot of problem in the life of these people. Why these have gone so first before heart, for example? Well, because the delivery is much easier, you know, you want to infect the liver, it's easier because everything goes eventually to the liver for being degraded. So, you know, so if you look at the timeline that is taken for these first therapies to come where they are now, I think that the heart is not on a slower pattern of development, you know, with all the complexity that there is in infecting the heart. Well, this has been fascinating. I didn't want to get into why did you pick this versus all the work you've done in Long QT, maybe that we'll pick that for another time, but I'm guessing if this works, it opens up the field for all these other genetic abnormalities of cardiac arrhythmias that you and others have so nicely laid out the clinical patterns for. Sylvia, this has been wonderful. I can't thank you enough. I want the listeners to realize that I'm in Indianapolis on Eastern Standard Time, and you're all the way in Milan, Italy. And to have done this at the end of a long working day, we can't thank you enough. Thanks a lot, Syl. Thank you very much. Thank you.
Video Summary
In this segment of EP on EP, Professor Sylvia Priori discusses her ongoing research on catecholaminergic polymorphic ventricular tachycardia (CPVT) and gene therapy. CPVT is a disease that can lead to sudden death in young adolescents and children. Professor Priori explains how her team identified the culprit gene for CPVT and the clinical manifestations of the disease. She also discusses current treatment options, such as beta blockers and flecainide, as well as the challenges in managing the disease. Professor Priori highlights the potential of gene therapy in providing a more permanent and radical solution for CPVT, and the progress made in preclinical models to test the efficacy and safety of this approach.
Keywords
catecholaminergic polymorphic ventricular tachycardia
gene therapy
sudden death
beta blockers
flecainide
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