Podcasts about niemann pick

Dr. Adrian Quartel, Chief Medical Officer at Zevra Therapeutics, has received FDA approval for their drug MIPLYFFA in combination with miglustat, the first treatment in the US for Niemann-Pick type C, an ultra-orphan disease. This hard to diagnose, rare genetic lysosomal storage disorder affects the recycling of cholesterol and lipids in cells, leading to neurological and physical problems. The Amplify Assist program has been set up to help patients access and afford the treatment. Adrian elaborates, "Niemann-Pick C is a very rare or ultra-orphan disease. It's one of what is considered a lysosomal storage disorder. I'll try to explain a little bit about what that means. So lysosomes are little organelles or little systems within the cell that are basically the waste disposal system from the cell. They break down worn-out parts on the inside of the cells, or they break down harmful molecules and waste products. They're effectively recycling materials in the cell. So, any lysosomal storage disorder actually affects the system where waste products are recycled within the cell. In Niemann-Pick C disease, it's specific for lipids such as cholesterol or sphingolipids inside the cell that need to be recycled."   "The early onset of the late infantile onset usually occurs before the age of 10. Then, you have the juvenile and adult-onset, which usually occurs after the age of 10 and have different types of symptoms. Once you have the neurological symptoms, they usually start with delay in motor milestones in the younger children. But most often, we see a diagnosis happening between the ages of, say, three and seven, starting with problems in walking, stability or gait problems, clumsiness, delay in speech, or losing the ability to speak appropriately, as well as seizures, problems at school, problems to follow direction at school, some behavioral problems." #ZevraTherapeutics #RareDisease #OrphanDisease #NiemannPick #NPC #NiemannPickAwareness #PediatricRareDisease zevra.com Download the transcript here

Dr. Adrian Quartel, Chief Medical Officer at Zevra Therapeutics, has received FDA approval for their drug MIPLYFFA in combination with miglustat, the first treatment in the US for Niemann-Pick type C, an ultra-orphan disease. This hard to diagnose, rare genetic lysosomal storage disorder affects the recycling of cholesterol and lipids in cells, leading to neurological and physical problems. The Amplify Assist program has been set up to help patients access and afford the treatment. Adrian elaborates, "Niemann-Pick C is a very rare or ultra-orphan disease. It's one of what is considered a lysosomal storage disorder. I'll try to explain a little bit about what that means. So lysosomes are little organelles or little systems within the cell that are basically the waste disposal system from the cell. They break down worn-out parts on the inside of the cells, or they break down harmful molecules and waste products. They're effectively recycling materials in the cell. So, any lysosomal storage disorder actually affects the system where waste products are recycled within the cell. In Niemann-Pick C disease, it's specific for lipids such as cholesterol or sphingolipids inside the cell that need to be recycled."   "The early onset of the late infantile onset usually occurs before the age of 10. Then, you have the juvenile and adult-onset, which usually occurs after the age of 10 and have different types of symptoms. Once you have the neurological symptoms, they usually start with delay in motor milestones in the younger children. But most often, we see a diagnosis happening between the ages of, say, three and seven, starting with problems in walking, stability or gait problems, clumsiness, delay in speech, or losing the ability to speak appropriately, as well as seizures, problems at school, problems to follow direction at school, some behavioral problems." #ZevraTherapeutics #RareDisease #OrphanDisease #NiemannPick #NPC #NiemannPickAwareness #PediatricRareDisease zevra.com Listen to the podcast here

Zevra Therapeutics, formerly KemPharm, rebranded itself in early 2023 following the acquisition of the experimental therapy arimoclomol for the rare lysosomal storage disorder Niemann-Pick type C. Zevra is Greek for “zebra,” a symbol of rare disease. The company subsequently built out its rare disease pipeline through the acquisition of Acer Therapeutics in November 2023. An FDA decision on arimoclomol is due by the end of September. We spoke to Neil McFarlane, president and CEO of Zevra Therapeutics, about Niemann-Pick type C disease, the FDA's upcoming decision on whether to approve the drug, and its broader efforts to build itself into a rare disease therapeutics company.

How can patients and their families become more integral in the clinical research process? How can patient-led research become more accepted in the scientific community? How are inspiring groups forging new, collaborative paths for science and medicine, and reshaping how medical research is conducted?  We will tackle those questions and much more in this episode with Amy Dockser Marcus, a Pulitzer Prize-winning journalist and author of the recently published book, “We the Scientists: How a daring team of parents and doctors forged a new path for medicine.” Amy is a veteran reporter at the Wall Street Journal and won her Pulitzer Prize for Beat Reporting in 2005 for her series of stories about cancer survivors and the social, economic, and health challenges they faced living with the disease. She has covered science and health at the Journal for years, and she also earned a Masters of Bioethics from Harvard Medical School.  -------------------------------------------------------- Episode Transcript: 00;00;00;00 - 00;00;24;19  How can patients and their families become the centers of research? What is open science and who are citizen scientists? We'll explore those questions and more on this episode of Research and Action in the lead in. Hello and welcome back to Research and Action, brought to you by Oracle Life Sciences. I'm your host, Mike Stiles, and our guest is Amy.     00;00;24;19 - 00;00;48;22  Dr. Marcus That's right, that Amy Marcus, the Pulitzer Prize winning journalist, reporter at the Wall Street Journal, a Pulitzer Prize, was won for her series of stories in 2005 about cancer survivors and the social and financial challenges of living with cancer. Her beat, as you would imagine, has long been science and health. And she holds a master's of bioethics from Harvard Medical School, and she's an author.     00;00;48;22 - 00;01;04;26  Her book is We The Scientists How a Daring Team of Parents and Doctors Forged a New Path for Medicine. So this should be interesting as we talk about collaborative, open science and the rise of citizen scientists and patient led research. So thanks for being with us, Amy.     00;01;05;01 - 00;01;06;22  I'm happy to speak with you today.     00;01;06;22 - 00;01;26;29  Great to have you. In your new book, you take readers through some really, frankly, heart wrenching experiences that patients and their families have gone through with a rare and devastating disease called Niemann-pick. Hopefully I'm pronouncing that correctly. Tell us about the book and that disease and what fascinated you about this story.     00;01;27;14 - 00;02;01;21  The origin of the book really is a personal story, which is my mother got diagnosed with a rare type of cancer. And when I tried to do research on her behalf, I started to learn how challenging it is to develop drugs for rare diseases. After she passed away, I took some time off from the Journal. I had a research grant from the Robert Wood Johnson Foundation and I started traveling around the country looking to see if there were new models that might accelerate drug discovery.     00;02;01;29 - 00;02;25;21  And during the course of that research, I was introduced to a group of parents whose children have this rare and fatal genetic disorder, NIEMANN-PICK type C disease. It's a cholesterol metabolism disorder, so the cholesterol doesn't get out of the lysosome and that compartment in the cell and it starts to build up and it causes all kinds of problems.     00;02;25;21 - 00;02;52;12  And the children eventually lose the ability to walk and to talk and to feed themselves. But the parents that I met wanted to do something novel. They had found a group of scientists and researchers and clinicians and even some policymakers in the government that wanted to work together as partners and to see if they could accelerate the search for a cure or an effective therapy for an epic disease.     00;02;52;19 - 00;02;58;11  And they let me follow along during the course of that partnership for over ten years.     00;02;58;24 - 00;03;05;24  That's amazing that you got that kind of insight. And what did you learn over the course of that ten years?     00;03;06;22 - 00;03;34;15  Well, I was really interested in how they saw the production of science in a different way. They all wanted to try to save or extend the children's lives The disagreements lay in. How do you go about prioritizing drugs? What amount of risk is a patient or a patient's family willing to take compared to the level of risk that a doctor or scientist wants the patients to take?     00;03;34;15 - 00;03;54;14  These sorts of tensions arose, I think, in part because they were modeling a new method of where the patients expertise was considered as valuable or even at the center of this of this project. And that's not usually how it is.     00;03;54;14 - 00;04;09;09  But that's rare, right? I mean, in our in the culture of our health care system, it's not really common that the patients input or the patients families input is invited at all.     00;04;09;19 - 00;04;34;11  Yeah, I think that that you're right about that. I mean, the traditional way of setting things up is that the scientists devise the hypotheses and they then construct trials in conjunction with clinicians and sometimes with pharmaceutical companies, of course. But in this particular collaboration that I was describing, the drug was not in the hands of a pharmaceutical company.     00;04;34;11 - 00;04;59;06  It was widely available. And so the partnership was truly about, you know, going to be conducted at the NIH. And therefore it gave the parent and the families, I think, more leeway to do this experimental idea. What if we all recognized each other's expertise? What if we all saw each other as equal partners? What if we got to weigh in?     00;04;59;13 - 00;05;20;24  Not in once. You've already set up the clinical trial, but at the very, very outset, when you're simply going through the scientific literature to come up with potential compounds, when you're thinking about what might work, when you're trying to prioritize what to do first, second and third, all of those things where patients don't always have a voice. But in this case they really did.     00;05;21;07 - 00;05;43;16  You know, we just had Hilary Hannah Ho on the show. She's secretary general of the Research Data Alliance, and we talked about open science and open data and how important all that is to getting the scientific breakthroughs that will actually help people and get to those breakthroughs faster. But open science can kind of be polarizing. There's some confusion around what exactly it means.     00;05;43;23 - 00;05;48;14  How would you define or describe open science and citizen scientists?     00;05;48;27 - 00;06;34;22  Yeah, I think that's a really good point, that there isn't one sort of accepted name and that there are many names and people use different phrases when they're thinking about different things. For me, I used the term patient LED research and I often use the term citizen science. And what I meant by that was, again, what we've been talking about from the outset, which is a recognition that the patient, the patient experience should be at the center of everything, a recognition that the patient and the families are experts, that they have the ability not only to be beneficiaries of scientific knowledge, but also creators of scientific knowledge.     00;06;34;27 - 00;06;46;15  And to me, that shift the idea that you can be a creator of scientific knowledge is the fundamental one that needs to happen if we're going to really reach the goals that I think we all want to reach.     00;06;46;29 - 00;07;11;10  So here's something we highlighted in your book. Quoting here Science is inherently a social enterprise. Yet too often scientists operate behind closed doors, removed from the very people they intend to help. That's struck me as kind of a mike drop statement with a lot of truth to it. But did the pandemic change anything? Was the work still removed from those patients on ventilators and ICU?     00;07;11;20 - 00;07;52;04  So I do make a point in the book to draw some parallels between the various patient led research movement experiences that I describe and the COVID 19 pandemic, and in particular the group of patients that call themselves long COVID patients, where they're suffering symptoms for many, many months. I argue that COVID allowed us in real time to to recognize that anyone can be an expert and that now that is something that it was easier to see during the pandemic because there was a novel virus, there weren't established experts yet.     00;07;52;14 - 00;08;25;28  And so while doctors and scientists and the government were scrambling to try to help patients, I think they also saw themselves for the first time as part of this effort to understand the disease. Together, there wasn't already an understanding of COVID 19. And so what I say in the book is that we can draw from from that experience and sort of take that part of it forward where we say patients should be at the center of things.     00;08;26;06 - 00;09;07;01  Patients are experts. Patients are able to identify things that many scientists or doctors didn't have time to recognize because they were they had to focus on trying to save lives and, you know, working in a vacuum at that point. So there also was a sense of urgency. Like one of the things that I was struck by during the pandemic as a as a science reporter was that scientists were able to put their papers online right away on these websites before it had gone through the full peer review process because it was recognized is so essential to get this information out there as quickly as possible.     00;09;07;09 - 00;09;29;16  And everyone understood that maybe there were going to be some mistakes. It wasn't fully vetted, but it was out there. Not only was it publicly available to the doctors and scientists who are also studying it, it was publicly available to patients and people who are simply interested. And long COVID patients organized themselves, did research on themselves, and they also published their papers on these websites.     00;09;29;16 - 00;09;43;22  I think those types of models where patient researchers can be contributors and can benefit from the information to fuel their own research, I think that should move forward and is it shouldn't be just a relic of the COVID 19 pandemic.     00;09;44;07 - 00;10;05;03  But what isn't there a risk of chaos a little bit? Because we're always told, hey, whatever condition you have, don't go Googling it on the Internet. You'll just go down a rabbit hole and, you know, worry about all these conditions that you may or may not have. So what is the risk of, like you said, mistakes and wrong information being published?     00;10;05;13 - 00;10;27;11  Well, even the traditional peer review process in science publishes papers that turn out to have mistakes in them. Papers are retracted all the time. And there is a well-known phenomenon that peer reviewed papers sometimes the results can't be replicated. I mean, that's the problem for science. I don't think that's a problem just for having patient researchers get involved.     00;10;27;28 - 00;10;54;27  I also think that the advice not to Google something is both old fashioned at this point and probably unrealistic given that almost all of us are connected in some way through the Internet. My sort of idea, rather, is that let's use the Internet and other methods to become better partners. Let's share good quality information online that people have access to.     00;10;55;06 - 00;11;20;20  Let's form partnerships where we can collaborate, where among experts, the people that I was talking to and interviewing and spending time with the parents, they weren't saying, Hey, we're trying to go it alone. We know everything. No, the opposite. What they were saying is we have very relevant and valuable information. We are experts because we live with this disease and we know what level of risk we're willing to tolerate.     00;11;20;20 - 00;11;43;28  And we do our own research. But we need partners who can also help us fill the gaps where we don't have knowledge. We want to collaborate with scientists, we want to collaborate with clinicians treating our children. We want to collaborate with government scientists who have access to data and and robots and things that we're not going to have in lab equipment that we don't have access to.     00;11;44;06 - 00;12;02;19  So no one's saying, go down a rabbit hole by yourself. What people are arguing is let's find ways to pool information, and by pooling everyone's information, we can sort through more quickly what's good, what we think is good, but might turn out not to be good later. And what can benefit all of us.     00;12;03;04 - 00;12;20;02  Yeah, and from a technology standpoint, gathering that data and organizing it and working with it is becoming more possible than ever. COVID should have scared our health system out of its mind. Did it? And is that leading to any systemic changes in science and health?     00;12;20;15 - 00;12;46;19  Well, I'd like to focus on what my book was focusing on, which is can a group of patient activists and scientists and clinicians and government policymakers working together make changes to the system? And I think the answer is yes. You can make changes to the system. The patient researchers that I was talking to and the families I was talking to, they built on activist patient work that had gone before.     00;12;46;19 - 00;13;10;06  And there have been responses in the past. HIV activists were able to influence the FDA to pass the accelerated approval rule that now allows drugs to be approved more quickly. And I think that, you know, compassionate use program that FDA has the patients in my family, the patients in my book and the families benefited from that as well.     00;13;10;17 - 00;13;48;01  So there have been changes along the way. But I think what my book is arguing for, and I think this message came out of the COVID 19 pandemic as well, is that even with all the changes that have been made in the past, the patient experience is still not at the heart of the system. And I think that's the message that all of these families are saying put the patient experience at the heart of things, and then you will see that the system, when you configure the system around the patient centric experience, you'll see that it will work in a different way and an I think, a better way.     00;13;48;02 - 00;13;50;02  But we need to run that experiment.     00;13;50;17 - 00;14;12;20  So we mentioned the concept of citizen scientists. That's what we've been talking about. These are people that pursue what they pursue, driven by mostly love and urgency for their kids, which is just a whole different level of motivation than most researchers have. I think you have a few stories about, you know, people like Chris and Hugh Hempel and and some others that went through this experience.     00;14;13;02 - 00;14;34;21  I want to make a point here that I think also is really important for people to understand who are listening to this. The parents in my book and you know, you cited Chris and Hugh, they were definitely among the pioneers who did this. And there was Phil and Andrea Morella, and there were also Darrel and Mark Poppea who are who are part of this, too.     00;14;34;21 - 00;14;57;29  And many, many other parents. I mean, the Parseghian Research Foundation and the National Niemann-pick Disease Foundation, all family driven. The people who are doing this. Yes, they are driven by their love of their children. They are driven by a sense of urgency. But they're not going to the FDA and saying, Hey, please pass and approve a drug because we love our children.     00;14;58;05 - 00;15;24;05  Please pass and approve a drug based on our emotion. No, not at all. They want to give effective drugs to their children. What they are saying is we are creating scientific knowledge and we think that that should be part of this approval process, that should be part of the drug development process. I just want to give some examples that I cite in the book where the parents were creators of scientific knowledge.     00;15;24;24 - 00;16;07;11  You had parents who read the scientific literature, published scientific literature, called up. The scientists interviewed the scientists came up with hypotheses themselves that they proposed to scientists, contributed to the two scientific experiments, coauthored papers that were published in the peer reviewed scientific literature. You know, went to the NIH regularly to have meetings where they helped contribute to assessing and prioritizing which compounds should go first in terms of advancing them into clinical trials, contributed their thoughts on the risk benefit analysis in devising the clinical trials.     00;16;07;22 - 00;16;34;28  One of the parents went to an FDA sponsored workshop for how to file an orphan drug designation, which is part of the approval process and the long process to getting approval for rare disease drugs. And went to the workshop, participated in the workshop, presented scientific data to the regulators, met with the regulators, and earned an orphan drug designation for one of the compound Cyclodextrin that got moved forward.     00;16;35;07 - 00;16;46;24  So yeah, they have a sense of urgency and yes, they love their children and want to save their lives, but they're producing real scientific knowledge and I really hope that that people take that message away from reading the book.     00;16;47;10 - 00;17;08;15  So those are great examples of exactly what citizen scientists do that sets them apart from just patients who are not doing that level of research, that depth of research. You talk about Chris Austin and the book, and I'm going to read another quick excerpt here, The Promise of Genetics to Deliver new interventions, new drugs and new treatments for patients is not going to happen.     00;17;08;15 - 00;17;27;28  Chris told his boss, unless there's some way to get through the valley of death. Francis gave Chris a green light to pursue his vision. So the boss in that excerpt is former National Institutes of Health director Francis Collins. What is the Valley of Death and Chris's role in citizen led research?     00;17;28;06 - 00;17;54;21  Great. No, that's a great question. So Chris Austin is a Harvard Medical School trained neurologist, also with a background in genetics who worked at pharmaceutical companies as well, and then found his way to the niche where he worked for Dr. Collins and became also a director of one of the institutes at NIH called Ed Katz, the National Center for Advancing Translational Science.     00;17;55;06 - 00;18;23;29  And one of the sort of green lights he got from Dr. Collins was to set up a lab that would have robots that were sort of at the same type of robots that pharmaceutical companies have that would work around the clock and could rapidly screen drugs to try to find compounds that might work for diseases. And what Chris Austin's idea was is that let's screen these vast libraries.     00;18;24;04 - 00;18;50;06  Let's find some drugs that might be promising, and let's also find patient partners. Let's find scientist partners, and let's then try to take all this data and move it forward together. One of the hypotheses that Chris Austin said he had as a scientist was can drug development go faster if patients and families are part of that process from the very beginning?     00;18;50;18 - 00;19;17;02  And one of the things that Chris Austin was trying to get around is this valley of death, which is this, you know, where compounds kind of go to die. You have a great idea as a scientist. But how do you get that idea from the bench to the clinic and to a patient's bedside? And the Valley of Death is just all the various obstacles that end up making it hard to develop a drug.     00;19;17;13 - 00;19;39;21  Some of it can be scientific. You know, you test it in a in a mouse or an animal, you test it in the lab and it turns out to be toxic for the cells or the amount of drug that you need to give to a person is so high it's not realistic or a drug company decides they want they don't want to put any money into it anymore or it gets or a drug company gets bought and they don't want to pursue it anymore.     00;19;39;21 - 00;20;02;08  And there's a million things that happen in the Valley of Death. But Chris Austin's vision was if we can involve patients and families as partners, along with scientists and drug developers and government officials from the beginning, maybe we can get things out of the Valley of Death, or maybe we can fail faster and find the successful compounds more quickly.     00;20;02;25 - 00;20;22;23  Yeah, a big takeaway from your book is the need to build bridges between science and citizens. But and we talked touched on this a little bit. You can't sacrifice scientific rigor or safety. So what are the challenges to building these bridges? What's holding that process back, especially when it does come to drug discovery and clinical trials?     00;20;23;09 - 00;20;47;05  So I think that there is a variety of issues that make it challenging to build bridges. For one thing, there's often a tension between, you know, people who are sick or are advocating on behalf of people who are sick, who really want to focus on the here and now. They they really need something to help their loved one right now.     00;20;47;19 - 00;21;22;19  And often, you know, clinical trials are an experiment. And when you enroll in a clinical trial, you're told this is not designed for the benefit of you. This is designed to benefit future patients. And therefore, it's not a treatment and it's not the equivalent of clinical care. And that can be a source of frustration and tension. And often also when research crews are doing research, they weigh the risk benefit assessment of moving drugs forward differently than people who are trying to you know, solve a problem now.     00;21;23;00 - 00;21;48;14  So I think that and that came up in this partnership in my book. It came up in this partnership in my book a lot. And yet I think each side was able to get a sense of what the points were, what the what the tensions were. But again, in my opinion, one of the ways that they overcame this divide was by both sides saying patient centric medicine is the way to go.     00;21;48;15 - 00;22;16;29  Patient centric science is the way to go. There are ways to collect data in a rigorous manner that can both benefit patients now and also not stop you from insights that will lead to benefits in the future. There are ways to come to terms with that. Some people have a higher acceptance of risk than others. I mean, we see movement towards that already right now.     00;22;17;01 - 00;22;23;01  I think that one of the messages of my book is to try to accelerate that even further.     00;22;23;25 - 00;22;37;19  Well, to that point, you say in the book, government and agencies like the FDA and NIH have a vested interest in helping these science and citizen partnerships succeed. Do they understand that? And what role should government be playing to move this forward?     00;22;38;01 - 00;22;57;01  Well, government is not one person. You know, so but I think that the book shows that there are people in the government who were partners with the patients and the families and the scientists and the clinicians. I mean, this whole book is about a partnership. And Chris Austin, although he's no longer in the government, he left the government.     00;22;57;10 - 00;23;28;05  He was in the government at the time, and he was a partner with these people. So I think that the government has shown in the book that, you know, and outside of my book, obviously interest in investing in new ways to do science, interest in investing in new ways to accelerate science, the government is supposed to represent the interests of the people, and the people's interest is in being healthy and in and trying to find solutions for drugs.     00;23;28;14 - 00;23;56;15  So in the book, I do talk about how the patients and the families in my book were able to directly talk to FDA regulators. Some of the parents went to workshops that the FDA was sponsoring. They had conversations with FDA regulators. I think those types of workshops are really novel and they really are fruitful because they allow the families and the patients to really think like scientists and to produce science as they can and should do.     00;23;56;16 - 00;24;21;16  They want to produce science. And I think also one of the messages that Chris Austin gave at representing the NIH was that the NIH is here to be your partner, and we're open to coming up with novel ways of accelerating science. So I think that there's there's openness to doing this, but of course, always more can be done.     00;24;21;17 - 00;24;51;16  I mean, patients have a sense of urgency, and that's the message that they bring to the government all the time. I mean, in the book, I, I describe FDA advisory committee hearings that are held when the FDA isn't sure about the data and they want to have a public hearing about it. And many of the parents and families showed up and gave testimony not just about their thoughts and their opinions, but about the data that they had gathered, the science that they were generating, that they wanted to share with the FDA and be heard.     00;24;52;00 - 00;25;16;13  What role does Rules Framework's guidelines play and what we're talking about here? I think you even your former advisor, was part of a group of scientists that worked on this framework. And the platform for patient led research, I think was spearheaded by that advisor, former advisor and a group of scientists. What's the infrastructure that needs to be put in place for this to work?     00;25;17;08 - 00;25;46;03  So, yes, So the advisor that you were referring to, Effie Diana was my advisor in my bioethics program and she does a lot of pioneering research on patient led research movements. And she and a group of collaborators, scientists and, and social scientists and clinicians and, and policymakers got together and tried to devise what they called a new social contract.     00;25;46;13 - 00;26;14;17  What they argued is, is that patient led research is a novel form of research that doesn't fit into the traditional regulatory standards that have guided, you know, clinical trials and human subjects research up until now. And that's because the traditional methods of regulation are based on the idea that scientists are going to be leading the research and doctors are going to be leading the research.     00;26;14;26 - 00;26;42;04  And that still is the traditional model. And they usually are leading the research. And in those cases, they often have more information and more power than the traditional patient or human subject. So Effie and her collaborators weren't arguing. We're arguing that the traditional rules should be thrown out because obviously patients do need protection and human subject research does need regulatory guidance.     00;26;42;11 - 00;27;17;26  But what she and the others were saying is let's also think about these new ways of doing research and how we can get scientists and clinicians to accept the results. That patient led research arrives at. And one of the ways she and the others said is let's come up with ways that patient researchers can seek ethical guidance. Let's put tools online that they can use so that they can devise experiments in ways that approach the rigor that traditional scientific experience experiments do.     00;27;18;06 - 00;27;52;04  Let's generate research that's of benefit to the people now, but also can be useful in guiding treatments in the future. Let's make a path towards publishing their data in peer reviewed journals. Let's make them part of the peer review process. I mean, you do have journals now that have patient researchers participating in peer review of scientific papers. And you have groups like Pachauri that ask scientists and patients to collaborate together on experiments.     00;27;52;13 - 00;28;24;24  So I think I think what she and the others were getting at is the current contract that we have may still be fine in certain circumstances, but isn't set up to address this new kind of research that's being done. And if we want it to be generalizable, scientific knowledge, which is always the gold standard, then we need to work together to help all of the partners to do better research that meets the standards that we can all except.     00;28;25;09 - 00;28;40;27  When you kind of make the promise of patient led research obvious. But, you know, how many times do we see things with great promise get tied up in knots? Is a paradigm shift likely? And if so, how long of a runway is that going to need?     00;28;41;15 - 00;29;01;11  I mean, I don't know how long it's going to take, but if there is a message in my book, if there is a message from the people that I focused on in my book, I mean, they've been working together for more than ten years. They've made a lot of progress, but they're not where they want to be yet.     00;29;01;20 - 00;29;23;29  So that's a long time. And I think that they want to go faster. I think the message of long COVID patients is we need to go faster. I think the message of HIV activists and breast cancer activists and disability activists is we need to go faster. And I don't think that you need to change a paradigm in a day.     00;29;24;12 - 00;29;53;19  Paradigms, by definition, take time to change, and they involve a lot of debate and discussion, dissension. And that's what happens in a society. People have different, different views. But I think what we're getting at here as a society is that patients need to be at the center of any paradigm that exists and that if everyone works together towards that goal, they may not agree how to get to that.     00;29;53;24 - 00;30;14;21  They may have different ideas on how to ensure that the science is rigorous and works. But if they keep this notion always at the center that the purpose is, is patient centered science, then I do think that you can end up with a paradigm that works better for more people.     00;30;15;16 - 00;30;27;10  One of the chapters in your book is Cathedral of Science, and in it a professor at Harvard. Had you read the story Cathedral by Raymond Carver. Why did they have you read that? And how does that relate to what we've been talking about?     00;30;28;04 - 00;30;55;26  Yeah, I mean, I say in the book that when we were told to read Cathedral by Raymond Carver, I was really surprised because usually in in my bioethics classes when we talk about stories and narrative bioethics, many of them involve sort of cases drawn from real life and cathedrals, really a quiet story that involves a married couple that seems to be drifting apart.     00;30;56;06 - 00;31;16;24  And the wife invites a friend who happens to be a blind man to come and stay with her and her husband. And the husband's a little bit jealous of the relationship that this person has with his wife and he doesn't really know what to say to him. And the wife goes to sleep and leaves these two men alone watching TV together.     00;31;17;00 - 00;31;38;19  And they start to watch a program about the building of a cathedral. And the narrator says to the blind man, Have you ever seen a cathedral? Do you know how to build a cathedral? And the blind man says, Let's draw one together. And the two of them construct a cathedral together. The man places his hand on the husband's hand, and they draw that cathedral.     00;31;38;27 - 00;32;01;23  And at the end of creating this cathedral, it's the blind man who says, Let's put some people inside, inside the cathedral. What's a cathedral without people? And I thought about this story all the time as I was spending time with the families and the scientists, because so many of the scientists were products of the Cathy trial of science.     00;32;01;23 - 00;32;34;13  They were the products of the best medical schools. They worked at the NIH. They I mean, they they really were, you know, part of this edifice that's been constructed and that has benefited so many people. And one of the things I kept thinking about is how do we put more people in this cathedral? I mean, that's really one of the messages that came through in this partnership that the parents and families and scientists and doctors and government officials were constructing a cathedral without people isn't really what you're looking for.     00;32;34;20 - 00;32;52;05  You're you're looking to use the power of science and research to help people. That's should be the goal of everything. And that's really the message I took from this story, that it touched me in just such a fundamental way. And it wasn't even a story about science.     00;32;53;27 - 00;32;57;18  As literature often does. That inspires us in many different ways.     00;32;57;21 - 00;32;58;20  Absolutely.     00;32;58;27 - 00;33;20;02  What did I miss? I mean, what is it that our listeners should know that you cover in the book that's important for them to know or some way that they can help or participate in this kind of effort? Or is there something that a follow up book might cover, something that you think needs additional exploration?     00;33;20;11 - 00;33;53;25  Well, I mean, I think that the message of the book is that we can all be scientists, right? I mean, it's in the title. We, the scientists, and I chose a title that echoes We the People, because I wanted people to think about the fact that what works best is a partnership. What works best is when we all come together and try to bring our different visions forward and to come up with something that will benefit all of us.     00;33;54;07 - 00;34;15;25  I think, you know, one of the things that I was struck by during during the research, not only for this book, but also when I, you know, covering health and science as a reporter is that all of us really are patients. We're either patients now or we were in the past or we will be in the future, or we love people who are patients.     00;34;16;04 - 00;34;50;28  We're advocates for those people, even if we're a doctor or a scientist, we're often on the other side of the table either trying to advocate for people we love or because we're patients. And so I think we all have a vested interest in creating a system that works well for all of us that remembers that we need treatments and that we that we need science and that all of us are experts in our own lives and that we can do research in a way that can contribute to advancing health and wellness for us all.     00;34;50;29 - 00;34;56;00  So I feel like that's the message that I hope is the takeaway of the book.     00;34;56;12 - 00;35;03;10  Well, I'm pretty sure there are listeners who are interested in the book and getting it or getting in touch with you. How can they do that?     00;35;04;00 - 00;35;26;00  So there are a variety of ways to get in touch with me. My email is publicly available. It's Amy Marcus at WSJ dot com. I'm on Twitter at Amy D Marcus. You can go into the bookstore and get the book, you know, in person, or you can order it online. You can get it from bookshop. You can get it from Powells.     00;35;26;00 - 00;35;32;18  You can get it from Amazon, Barnes and Noble. I mean, they're, you know, any, any, any place online. You can order the book.     00;35;32;26 - 00;36;03;05  Great. We appreciate that. And we want to thank you for being faithful listeners to Oracle Life Sciences, Research and Action. As always, we invite you to subscribe so you don't miss a single episode. And also maybe tell your friends and colleagues about the show as well. And we'll be back next time with more research and action.

En su serie de historias de la medicina, Cancho narra la historia de las gemelas Hempel, que sufrieron una enfermedad rara y hereditaria llamada Niemann-Pick.

En su serie de historias de la medicina, Cancho narra la historia de las gemelas Hempel, que sufrieron una enfermedad rara y hereditaria llamada Niemann-Pick.

This time on the Anatomy in Clay® Learning System podcast, the guests are two assistant professors of biology from Winthrop University in South Carolina.  After earning a Ph.D. from the University of Campinas in Sao Paulo, Brazil, Silvia Wozniak became a post-doctoral fellow at the Department of Neurology at New York University, where she worked with lysosomal storage diseases diagnosis. A year later she moved to the Department of Human Genetics at Mount Sinai School of Medicine in New York to work on the development of therapy for Niemann-Pick disease. Wozniak joined Winthrop University n 2000. Jena Chojnowski earned her Ph.D in Zoology at the University of Florida. Her postdoctoral research studies were at the University of Georgia working on development of the thymus and eye. In January 2023, she joined the Winthrop University Biology department team. Her research consists of two main areas of interest: developmental biology and stem cell biology. She focuses on a developmental comparative anatomy approach to understand how one organ that accomplishes one goal, to detect light and convert it into electro-chemical impulses in neurons, can be utilized in so many diverse ways.  More: Intro and Outro music "Vicious Pen" courtesy of Moby Gratis

In this episode, we review the high-yield topic of Niemann-Pick Disease⁠ ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠from the Pediatrics section. Follow ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠Medbullets⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ on social media: Facebook: www.facebook.com/medbullets Instagram: www.instagram.com/medbulletsofficial Twitter: www.twitter.com/medbullets

Amy Dockser Marcus, in her new book We the Scientists, tells the story of a group of parents of children diagnosed with the rare and fatal genetic lysosomal storage disorder Niemann-Pick disease type C. When they were confronted with the fact that no treatment existed or would likely be developed in time to save the lives of their kids, they began collaborating with themselves, researchers, and physicians to accelerate the path to a treatment. We spoke Marcus about the lessons learned from the experience of the Niemann-Pick disease type C community, how these parents took an active role in the drug development process as citizen scientists, and how their efforts reflect a broader change in the way biomedical research is conducted.

Rich Pascoe, CEO of Zevra Therapeutics, is working with a team with deep experience developing drugs and getting them approved by the FDA.  Having developed multiple prodrugs for pain and ADHD, Zevra is now developing rare disease therapies with an initial focus on Niemann Pick Disease Type C and idiopathic hypersomnia.   Rich explains, "Our lead product is a drug called arimoclomol. It's intended for the treatment of Niemann Pick Type C disease, or NPC for short. Niemann Pick primarily affects children. It's a lysosomal storage disorder condition, meaning patients lack the ability to break down certain things, including cholesterol. As a result, they develop a myriad of symptoms that ultimately lead to, in most cases, the patient's death. The issues they deal with revolve around loss of ambulation and the ability to swallow, and it affects their cognitive function. It's a progressive disease, and oftentimes, it can advance very rapidly." "A little history on arimoclomol. The drug was previously in the hands of a company out of Denmark. We acquired the asset last year from that company along with some of the individuals at the company that are critical for the success of the product going forward." "In that setting, Orphazyme, the company that had the drug before us, had submitted it for approval here in the US with the FDA. The FDA rejected that approval request based on a number of factors that we have subsequently been working to address. We believe that given our track record as a company of being able to work with the FDA to get drugs approved, in some cases under some very challenging circumstances, that we are well-equipped to handle and manage this submission."  @Zevratx #ZevraTherapeutics #RareDisease #RareSleepDisorders #NiemannPickDiseaseC #IdiopathicHypersomnia zevra.com  Download the transcript here  

Rich Pascoe, CEO of Zevra Therapeutics, is working with a team with deep experience developing drugs and getting them approved by the FDA.  Having developed multiple prodrugs for pain and ADHD, Zevra is now developing rare disease therapies with an initial focus on Niemann Pick Disease Type C and idiopathic hypersomnia.   Rich explains, "Our lead product is a drug called arimoclomol. It's intended for the treatment of Niemann Pick Type C disease, or NPC for short. Niemann Pick primarily affects children. It's a lysosomal storage disorder condition, meaning patients lack the ability to break down certain things, including cholesterol. As a result, they develop a myriad of symptoms that ultimately lead to, in most cases, the patient's death. The issues they deal with revolve around loss of ambulation and the ability to swallow, and it affects their cognitive function. It's a progressive disease, and oftentimes, it can advance very rapidly." "A little history on arimoclomol. The drug was previously in the hands of a company out of Denmark. We acquired the asset last year from that company along with some of the individuals at the company that are critical for the success of the product going forward." "In that setting, Orphazyme, the company that had the drug before us, had submitted it for approval here in the US with the FDA. The FDA rejected that approval request based on a number of factors that we have subsequently been working to address. We believe that given our track record as a company of being able to work with the FDA to get drugs approved, in some cases under some very challenging circumstances, that we are well-equipped to handle and manage this submission."  @Zevratx #ZevraTherapeutics #RareDisease #RareSleepDisorders #NiemannPickDiseaseC #IdiopathicHypersomnia zevra.com  Listen to the podcast here

0:58 Labiotech.eu news2:37 Replay23:45 Azafaros39:39 GRO BiosciencesAs February 28 is Rare Disease Day, we have three guests on the podcast today all relevant to rare diseases. And they are Dan Mandell, CEO and co-founder of GRO Biosciences; Stefano Portolano, chief executive officer, Azafaros; and from Replay, Adrian Woolfson, executive chairman, president, and co-founder, and Lachlan MacKinnon, CEO and co-founder.Rare Disease DayTaking place on February 28 each year, the event raises awareness and looks to generate change for the 300 million people worldwide living with a rare disease, as well as their families and carers.This year, the day will be marked by more than 600 events in 106 countries.Replay and The University of Texas MD Anderson Cancer Center create SyenaReplay, a genome writing company reprogramming biology by writing and delivering big DNA, and The University of Texas MD Anderson Cancer Center, have launched Syena, a new oncology-focused product company pioneering T-cell receptor (TCR) natural killer (NK) cell therapies (TCR-NKs).Building on the intellectual property and technology from MD Anderson and Replay, Syena has the potential to create the next generation of cell therapy.AzafarosAzafaros is a clinical stage company founded in 2018 with a deep understanding of rare genetic disease mechanisms, and a compound library from Leiden University. Its aim is to build a pipeline of disease-modifying therapeutics to offer patients and their families new treatment options. The company's lead clinical-staged program is AZ-3102, a small molecule, orally available, brain penetrant azasugar, with the potential to treat GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) and Niemann-Pick disease type C (NP-C). This week, the company announced it has been granted two Rare Pediatric Disease Designations (RPDD) by the United States Food and Drug Administration (FDA) for the treatment of GM1 and GM2 gangliosidoses, Orphan Medicinal Product Designation (OMPD) by the European Medicines Agency (EMA) for the treatment of GM2 gangliosidosis, and an Innovation Passport by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of GM1 and GM2 gangliosidoses.GRO BiosciencesGRO Biosciences is leveraging groundbreaking science to expand the amino acid alphabet and deliver on protein therapeutics. The U.S. company is transforming treatments for increasingly prevalent chronic medical conditions including autoimmune and metabolic diseases to improve the lives of patients. GRObio is applying its platform to advance partnered and collaborative programs, as well as its own pipeline of protein therapeutics bearing unique NSAA (non-standard amino acid) chemistries. The company's NSAA therapeutics feature previously unattainable capabilities including unprecedented duration of action and precise regulation of the immune system.

$5 Q-BANK: https://www.patreon.com/highyieldfamilymedicine Intro 0:30, Galactosemia 1:36, Hereditary fructose intolerance 3:37, Essential fructosuria 4:21, Glycogen storage diseases 4:43, Period Acid Schiff and Diastase test (PAS-D) 5:57, Von Gierke disease 5:13, Pompe disease 6:33, Cori disease 7:41, Andersen disease 8:16, McArdle disease 8:56, Phenylketonuria 11:05, Alkaptonuria 12:56, Maple syrup urine disease 14:14, Homocystinuria 15:56, Urea cycle disorders 17:35, Fatty acid metabolism disorders 19:09, Lysosomal storage diseases 20:25, Tay-Sachs disease 20:53, Niemann-Pick disease 22:02, Gaucher disease 22:39, Metachromatic leukodystrophy 23:34, Krabbe disease 24:36, Hurler disease and Hunter disease 25:36 Fabry disease 26:28, Lesch-Nyhan syndrome 27:26, Adenosine deaminase deficiency 28:15, Practice questions 28:42

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.16.516777v1?rss=1 Authors: Pipalia, N. H., Huang, A. Y., Ralph, H. S., Maxfield, F. R. Abstract: Although considerable progress has been made in finding a therapy for Niemann-Pick type C1 (NPC1) disease, there still is no effective approved treatment. Previously, we reported results from a small molecule screen that was conducted on Chinese Hamster Ovary (CHO) cells (CT60) that lacked NPC1 expression. The hit compounds that were effective in reducing cholesterol accumulation in CT60 cells were not effective on human cells bearing disease causing mutations in NPC1. Hence, we conducted a new small molecule screen on patient-derived NPC1 skin fibroblasts using a combinatorial library of ~48,000 compounds. We have identified several compounds that corrected the phenotype in human heterozygous mutant NPC1 skin fibroblasts (GM03123) bearing the inactivating I1061T mutation in one allele and another set of inactivating mutations in the other. Among the hit compounds were several histone deacetylase inhibitors, which we have explored further and reported previously. With the determination of the structure of NPC1 protein and the development of computational docking algorithms, it seems worthwhile to show the structures of 128 compounds that reproducibly reduced cholesterol storage in mutant NPC1 fibroblasts but with no known mechanism of action. These compounds were not toxic and specifically effective on mutant cells but not on NPC1-/- cells, indicating on-target effect directly or indirectly. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr Marc Patterson and Dr Eugen Mengel explain the challenges of treating Niemann Pick Type C. Recent studies have shown the efficacy of Miglustat and Arimoclomal but they may end up forming just part of the puzzle being built to manage this condition. Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment Eugen Mengel, et al https://doi.org/10.1002/jimd.12428 Long-term survival outcomes of patients with Niemann-Pick disease type C receiving miglustat treatment: A large retrospective observational study Marc C. Patterson, et al https://doi.org/10.1002/jimd.12245

Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins y Cotran. Patología estructural y funcional. Elsevier Health Sciences Spain. --- Send in a voice message: https://anchor.fm/las-poderosas-celulas-nk/message

Sharon Hrynkow, PhD, joins the Rare Disease Report to discuss the ultra rare and heterogenous lysosomal storage disorder. 

US stock futures keep falling and the Dow might have its worst week since January.Here's what is happening in the markets today, Friday, June 18th.The Dow has lost 1.9% week to date, on pace for its worst week since January.The S&P 500 has fallen 0.6%. But the Nasdaq has gained 0.65% on the week.The Fed moved up its timeline for rate hikes, seeing two increases in 2023 after Powell said in March that he saw no increases until at least 2024. But the fact that Powell also did not discuss tapering (even taking it out of the vocabulary), could signal expansionary policy is here to stay for the next while. That's in addition to the "transitory" inflation outlook, which is starting to take root among the investing community.Investors see inflation as transitory, too. This means: Out of value stocks and into growth stocks. Gold fell below 1,800.Smith & Wesson (SWBI) reported better-than-expected profit and sales for its latest quarter, as the gun maker's sales surged 67% compared to the same quarter a year earlier. The company notes that its shipments jumped 70% compared to overall industry growth of 42%. Shares rallied 4.7% in premarket trading.Orphazyme (ORPH) plunged 52.6% in the premarket after the Food and Drug Administration rejected its experimental treatment for a genetic disorder known as Niemann-Pick disease type C.Citigroup (C) – The bank's stock remains on watch after declining for the past 11 consecutive trading days, losing 14% over that time.New national holiday: Juneteenth = June 19th. Union General Gordon Granger arrived with federal troops in Galveston, Texas, and issued an order freeing the last of America's slaves. This is the 12th national holiday.This wraps up today's stock market news.If you enjoyed the "Stock Market Today" video, make sure to subscribe to this podcast. And for more stock market news,  visit https://rockwelltrading.com.#todaysstockmarket #stockmarkettoday #stockmarket

Guest: Caroline Hastings, MD Guest: Raymond Y. Wang, MD Niemann-Pick disease type C (NPC) is an ultra-rare, inherited, neurodegenerative disease with life-threatening complications. Due to its highly variable onset of neurological symptoms throughout one's lifespan, recognizing and establishing diagnosis for NPC can be challenging for any clinician. That's why Drs. Caroline Hastings and Raymond Y. Wang join Dr. Jennifer Caudle to help address those challenges with a detailed look at this genetic condition, the factors underlying its variable onset and course, and strategies to improve recognition, cross-specialty communications, and time to diagnosis. Copyright ©2021 Orphazyme A/S. All rights reserved.NP-USA-1492-v1ORPHAZYME is a trademark or registered trademark of Orphazyme A/S.

Guest: Caroline Hastings, MD Guest: Raymond Y. Wang, MD Niemann-Pick disease type C (NPC) is an ultra-rare, inherited, neurodegenerative disease with life-threatening complications. Due to its highly variable onset of neurological symptoms throughout one's lifespan, recognizing and establishing diagnosis for NPC can be challenging for any clinician. That's why Drs. Caroline Hastings and Raymond Y. Wang join Dr. Jennifer Caudle to help address those challenges with a detailed look at this genetic condition, the factors underlying its variable onset and course, and strategies to improve recognition, cross-specialty communications, and time to diagnosis. Copyright ©2021 Orphazyme A/S. All rights reserved.NP-USA-1492-v1ORPHAZYME is a trademark or registered trademark of Orphazyme A/S.

De causa genética, a enfermidade é rara, incurável e se manifesta de três formas diferentes

De causa genética, a enfermidade é rara, incurável e se manifesta de três formas diferentes

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.06.369447v1?rss=1 Authors: Angelini, R., Yutuc, E., Wyatt, M. F., Newton, J., Yusuf, F. A., Griffiths, L., Cooze, B. J., El Assad, D., Frache, G., Rao, W., Allen, L. B., Korade, Z., Nguyen, T. T., Rathnayake, R. A., Cologna, S. M., Howell, O. W., Clench, M. R., Wang, Y., Griffiths, W. J. Abstract: Despite being a critical molecule for neurobiology and brain health, mass spectrometry imaging (MSI) of cholesterol has been under reported compared to other lipids, due to the difficulty in ionising the sterol molecule. In the present work we have employed an on-tissue enzyme-assisted derivatisation strategy to improve detection of cholesterol in brain tissue sections. We report distribution and levels of cholesterol across specific brain structures of the mouse brain, in a model of Niemann-Pick type C1 (NPC1) disease, and during brain development. MSI revealed how cholesterol changes during development and that in the adult is highest in pons and medulla of the brain stem. Cholesterol was significantly reduced in the corpus callosum and other brain regions in the Npc1 null mouse, confirming hypomyelination at the molecular level. Our study demonstrates the potential of MSI to the study of sterols in neuroscience. Copy rights belong to original authors. Visit the link for more info

Niemann-Pick disease is a rare and often-fatal genetic, metabolic disorder with no approved treatments, but that could soon change as new therapies advance through the development and approval process. In anticipation of the first therapies for the disorder becoming available, the National Niemann-Pick Disease Foundation has been working to prepare patients and their families for new obstacles they may need to navigate to obtain access and reimbursement for these treatments. We spoke to Joslyn Crowe, executive director of the National Niemann-Pick Disease Foundation, about what her organization is doing to prepare the community for the availability of the first therapies for the conditions, the issues people will need to consider, and how families may need to think differently about their futures.

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley from VCU Health, the Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Our feature paper today is very important and pertinent to the times, talking about the multi-system inflammatory syndrome in children in our current global SARS coronavirus 2 pandemic. Really, really important stuff, but you have to hold on, listen with us to this summary which is full of really exciting papers. You know what, Greg? I'm going to start. So what do you know about the rostral medial prefrontal cortex of our brains? Dr Greg Hundley: Well, let's see. I wonder if it has anything to do with emotion or stress maybe? Dr Carolyn Lam: Oh, you're too smart. Either that or that coffee is loaded. Very good answer. The rostral medial prefrontal cortex is an important brain region that processes stress and regulates immune and autonomic functions. Now, since psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease, our authors today, Dr Shah and colleagues from Rollins School of Public Health, Emory University, hypothesize that changes in the rostral medial prefrontal cortex activity with emotional stress may be informative for future risk of MACE or major adverse cardiovascular events. They examined 148 participants with stable coronary artery disease who underwent acute mental stress testing using a series of standardized speech or arithmetic stressors and simultaneous brain imaging with high resolution positron emission tomography brain imaging. They defined high rostral medial prefrontal cortex activation as a difference between stress and control scans greater than the median value for the entire cohort. They also measured interleukin-6 levels 90 minutes post stress and high frequency heart rate variability during stress. Dr Greg Hundley: Wow, Carolyn, what an intriguing article correlating the imaging findings with stress and systemic inflammation. What did they find? Dr Carolyn Lam: So they found that higher roster medial prefrontal cortex activity with mental stress was independently associated with higher risk of major adverse cardiovascular events. Immune and autonomic responses to mental stress contributed to the increased of adverse events among those with the higher stress reactivity. Stress-induced activation may therefore represent a new method of risk stratification of individuals with coronary artery disease. Dr Greg Hundley: Very nice. That really ties a lot together. Makes a lot of sense, Carolyn. Well, my first paper is from Dr Patrick Ellinor from Massachusetts General Hospital and the Harvard Medical School, but first Carolyn a quiz. So here's the background to the quiz. I'm going to talk about the heart myocytes versus the fibroblast versus the microcirculatory cells. So within each of those groups, Carolyn, this is a way or no way, are all the cell types the same? Dr Carolyn Lam: Well, at embryonic stage maybe? All right, I'll be superficial about it. No way, they're different. Dr Greg Hundley: Very good, Carolyn. These authors applied recent advances in low input RNA sequencing that allowed definitions of cellular transcriptome to assess the cellular and transcriptional diversity of the non-failing human heart. Dr Carolyn Lam: Wow. What did they find? Dr Greg Hundley: Carolyn, the author sequences the transcriptomes of 287,269 single cardiac nuclei, revealing a total of nine major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses included two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblast subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in the extracellular matrix remodeling and vascularization. Using genetic association data, the authors identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Therefore, Carolyn, the authors' identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases. Dr Carolyn Lam: Okay, I have to admit that's a lot more diversity than I anticipated. Very cool, Greg. Ha, I got a question for you. What do you think of abdominal aortic aneurysms and Niemann-Pick disease have in common? Dr Greg Hundley: I definitely need phone a friend. Dr Carolyn Lam: Here, let me tell you about it. The link is in transcription factor EB. Now what is transcription factor EB? It's a master regulator of lysosome biogenesis that has beneficial effects on lysosomal storage diseases. Now, Dr Fan from University of Cincinnati College of Medicine and Dr Chen from University of Michigan Medical Center are co-corresponding authors of this paper and they and their coauthors found that transcription factor EB expression was reduced in human aneurysms. Vascular smooth muscle cells selective knockout promoted abdominal aortic aneurysm development via induction of vascular smooth muscle cell apoptosis in mice. In addition, they found that 2-hydroxypropyl beta cyclodextrin, which is an FDA approved cyclodextrin derivative currently used to increase the solubility of drugs and under phase two clinical trial to treat Niemann-Pick disease type C1. So they found that this compound activates transcription factor EB and inhibits abdominal aortic aneurysm in multiple mouse models. So these findings intriguingly demonstrate the potential use of transcription factor EB activators to treat abdominal aortic aneurysms. Dr Greg Hundley: I don't think I would've gotten that quiz right for sure. My next paper is from Professor Marco Valgimigli from the University of Bern. It's entitled "Cangrelor Tirofiban and Chewed or Standard Prasugrel Regimens in Patients with ST Segment Elevation Myocardial Infarction". These are the primary results of the Fabulous Faster trial. Since the standard administration of newer oral P2Y12 inhibitors, including Prasugrel or Ticagrelor provides suboptimal early inhibition of platelet aggregation in ST segment elevation myocardial infarction patients undergoing primary PCI. These authors sought to investigate the effects of Cangrelor, Tirofiban, and Prasugrel administered as chewed or integral loading dose on inhibition of platelet aggregation in patients undergoing primary PCI. Dr Carolyn Lam: Ah. So what was the design of this study and who did they enroll, Greg? Dr Greg Hundley: Carolyn, a total of 122 P2Y12 naive ST elevation myocardial infarction patients were randomly allocated one to one to one to Cangrelor, 40 subjects, Tirofiban, 40 subjects, both administered as bolus and two hour infusion followed by 60 milligrams of Prasugrel or 60 milligram loading dose of Prasugrel, 42. The latter group underwent an immediate one-to-one some randomization to chewed, so 21 subjects there, or integral, 21 subjects there, tablets administration. The trial was powered to test three hypotheses: non-inferiority of Cangrelor compared with Tirofiban using a noninferiority margin of 9%. Second, superiority of both Tirofiban and Cangrelor compared with chewed Prasugrel. And finally, superiority of chewed Prasugrel as compared with integral Prasugrel, each with an alpha of 0.016 for the primary end point that was 30 minute inhibition of platelet aggregation at light transmittance aggregometry in response to 20 micromoles per liter of adenosine diphosphate. Dr Carolyn Lam: Wow. A comprehensive study. Okay, so what did they find? Dr Greg Hundley: Well, Carolyn. Cangrelor proved inferior on inhibition of platelet aggregation compared with Tirofiban. Next, both treatments yielded greater on inhibition of platelet aggregation compared with chewed Prasugrel which led to higher active metabolite concentration, but not greater inhibition of platelet aggregation compared with integral Prasugrel. Therefore, Carolyn, Tirofiban by exerting more potent and consistent innovation of platelet aggregation may be more effective than Cangrelor in reducing the risk of acute ischemic complications. Now, all of these results need to be further ascertain in the context of studies powered for clinical end points. Dr Carolyn Lam: Thanks, Greg. All right, well, let's sum up what else is in this issue. I've got few papers really related to COVID-19. First as a perspective by Dr Oudit on ACE2: A Double-Edged Sword. Then we have an On My Mind paper by Dr Kevin Shah titled Tissue is the Issue, Even During a Pandemic. We have a research letter by Dr Adusumalli on Telemedicine Outpatient Cardiovascular Care During the COVID-19 Pandemic, is this bridging or opening the digital divide? And finally, another research letter by Dr Priori on the association of hydroxychloroquine with QT interval in patients with COVID-19. Dr Greg Hundley: Very good, Carolyn. Well, I've got a couple extra papers as well. The first is an exchange of letters between Dr Ji-jin Zhu and our own Dr James de Lemos regarding the article Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study. Also, Dr Daniel Schimmel has a case series entitled Not for the Faint of Heart: A Rapidly Evolving Case of Syncope During Pregnancy. And then finally, Dr Michael Sayre has a research letter focusing on the prevalence of COVID-19 in out of hospital cardiac arrest, implications for bystander CPR. Dr Carolyn Lam: Nice Greg. Well, let's hop on to the feature discussion, shall we? Dr Greg Hundley: You bet. Dr Carolyn Lam: We've been hearing a lot about the COVID-19 pandemic and its effects in adults, but today's feature paper deals with the so important and topical issue of the multi-system inflammatory syndrome in children in the context of this COVID-19 pandemic. I am so pleased to have with us the corresponding author of today's feature paper, Dr Damien Bonnet from the Necker Sick Children's, University of Paris, as well as our associate editor, Dr Gerald Greil from UT Southwestern. Damien, thank you so much for this very, very important study. Everyone's been looking for data, and I truly think yours are just the definitive ones that we have now, but please tell us a bit about the study and what you found. Dr Damien Bonnet: In Paris, we have been alerted by an increase of admission of children with acute heart failure in context of long-lasting fever with different organ involvement. So we started in mid-April to signal to our health authorities that there was an emerging entity. Since then we have seen these rare entity about 100 of times in various areas. So it's so rare entity because there are 3 million children living in my area. And this syndrome is composed of different signs. The first one is a high fever lasting for more than three days, gastrointestinal or digestive symptoms, sometimes skin anomalies, heart arrhythmia, and of course heart failure with sometimes shock. So this syndrome has some similarities with a known other syndrome that is Kawasaki disease that we all know in pediatric cardiology. And we will discuss that later, I think. It's certainly a different entity. So we started to treat them as if they were Kawasaki-like disease with immune blood splints and the majority of them improved rapidly with this type of treatment. And while some of them were on ECMO at baseline or in severe condition, they all improved. And fortunately in my institution did not have any dead. So that's the summary of what we have submitted to circulation. Dr Carolyn Lam: Thank you so much, Gerald, could you help frame for us once again how important this study is, and this condition is to recognize? And then I know you've got some questions for Damien too. Dr Gerald Greil: Thank you so much, Damien, for submitting your work to circulation and the reason why we all thought it's particularly important because you guys in Europe got the first rife. In the United States, North America, South America, kind of getting confronted with all these patients. And we are all very keen to learn from you. And obviously one of the first things when we get confronted with these patients now is how are we going to treat them? You mentioned IVIG as a possibility, I'm sure you have other options or experiences. Can you explain what is your evidence and how did you choose current treatment strategies? Dr Damien Bonnet: I think that at baseline, we used the IVIG because these patients resemble those with Kawasaki disease shock. Certainly today there has been different reports and the spectrum of clinical signs and biological anomalies in this syndrome differ from that of Kawasaki. But still the treatment with anti-inflammatory agents, IVIG, or other agents has the objective to accelerate recovery and potentially to prevent cardiac injury in Kawasaki disease. We have not demonstrated that in the present entity. So there is today, I think no evidence to say that IVIG should be given to all patients with this disease. But certainly treating the severe inflammation as an impact in cardiac function. Dr Gerald Greil: We were kind of reminded when you saw these patients of Kawasaki disease, which is probably every pediatrician, pediatric cardiologist has a similar idea when you see these patients. Is it Kawasaki disease? Is it not? Dr Damien Bonnet: I think that we have to balance the answer. There are some clinical signs that are shared between the multisystem inflammatory syndrome and Kawasaki disease. The continuous signs, the lymphadenopathies with fever, but the inflammation is much more intense in this entity and the other aspect is Kawasaki disease mainly involves arteries, as in arthritis. And this syndrome is mainly affecting the mitochondria. That's what, at least what we see today. What we don't have is the late outcome. But today, at least in the patient that we have seen in Paris, we have not seen a high prevalence of coronary artery involvement, both at initial phase and later on. I think that the mechanism, the exaggerated inflammation, and the deleterious effect on myocardium of this inflammatory storm, has similarities with that of Kawasaki disease. Dr Gerald Greil: So since you've got a lot of experience, can you just summarize for us, how do you treat these patients once they come into your hospital? So we have a little bit of a guideline, but the current state of the arts. Dr Damien Bonnet: The paper that we are discussing today does not include all categories of patients with this syndrome. We included in this paper only patients who were admitted for acute heart failure, but today we have seen children with less severe disease. So when we admit them in Paris, we systematically dose BNP or anticrobian B depending on the institution. And if it is abnormal, we check the echo. And if the echo is abnormal, we will treat all of them with IVIG. That's the treatment that we do. If they are in shock, we associate IVIG and steroids. Today, I cannot say that it is a precise guideline two fold. It’s just our experience and we have not observed any fatalities. And the older patients recovered quite rapidly, let's say within a week for the majority of them. Dr Gerald Greil: So what do you think are the next steps? I mean, we collected from different institutions around the world their experience with this kind of type of disease. It seems to become more prevalent. What do you think is the next step for us as physicians in the scientific community? Dr Damien Bonnet: And that there are clinical issues. So the first one is to see or to look at potential cardiac residual anomalies, mitochondrial or coronary arteries aneurism, because today we have not precise information of that. The second is probably observational because it will be difficult to randomize young children, is what is the optimal treatment at baseline or what is the optimal strategy? And is it possible to stratify the strategy as I just said, but I don't have evidence for that. And for the long term, I think that trying to identify why only some children have this disease and why the other don't have, if there is any genetic susceptibility, it will be something interesting. And potentially as we discussed already together, it might give us some keys to better understand Kawasaki disease as well. Dr Gerald Greil: Thank you so much for summarizing that. I mean, we are all very much looking forward to working together with you and other groups around the world to get a little bit more and better insight in this kind of type of disease and how to treat them best and how to follow them up best. Dr Carolyn Lam: Thank you so much, Damien and Gerald. I mean, I'm sure I speak behalf of the entire audience that I learned a lot just listening to your very open and honest conversation of what we've seen, what we've experienced, what we don't yet know. Listeners, you have to refer to a beautiful accompanying editorial that Gerald invited, and it is by Dr John Simpson and Dr Jane Newburger from Evalina London Children's Hospital and Harvard Medical School, respectively. Thank you so much for joining us today. And please remember, you've been listening to Circulation on the Run. Tune in again next week. Dr Greg Hundley: This program is copyright the American Heart Association, 2020.  

Dr. Ileana Soto is an Assistant Professor in the Department of Molecular and Cellular Biosciences at Rowan University. She studies how disruption of brain development leads to neurological and neurodevelopmental disorders. Her goal is to identify defects at the cellular level before signs and symptoms of the disease can be detected. These defects may be promising targets for early treatment and prevention. Much of Ileana’s work focuses on Niemann-Pick disease type C. This is a rare neurodegenerative disease that causes dementia in children. When Ileana isn’t doing research or teaching, she enjoys going out to dinner and spending quality time with friends and family. Ileana also always looks forward to road trips with her family where they can visit new places, explore nature, go hiking, ride bikes, and recharge. She received her BS in general sciences and her PhD in biology from the University of Puerto Rico. Afterwards, she conducted postdoctoral research at Johns Hopkins University and The Jackson Laboratory before joining the faculty at Rowan University. Ileana was recently recognized for her work with the receipt of a National Science Foundation CAREER Award. In our interview, Ileana shares more about her life and research.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Go online to PeerView.com/NPH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Chronic visceral acid sphingomyelinase deficiency (ASMD), also referred to as Niemann-Pick disease type B, is a rare and progressive autosomal recessive lysosomal storage disorder that causes progressive accumulation of sphingomyelin and other lipids in tissues throughout the body and is associated with significant morbidity and reduced life expectancy. The diagnosis of chronic visceral ASMD is often delayed by months or years, because its complex signs and symptoms overlap with other diseases. In this activity, leading experts review current consensus recommendations for the diagnosis of ASMD in pediatric and adult patients. The faculty also review the latest safety, efficacy, and tolerability data on emerging therapies and explore patient cases to offer practical strategies on how to optimally manage patients with chronic visceral ASMD. Upon completion of this activity, participants should be better able to: Diagnose individuals with ASMD through the application of recent consensus recommendations, Cite available efficacy, safety, and tolerability data on emerging therapeutic modalities for the treatment of patients with ASMD, Examine the potential impact that ongoing clinical trials of emerging therapeutic approaches may have on the future treatment of patients with ASMD.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.20.105973v1?rss=1 Authors: Kaya, E., Smith, D., Smith, C., Morris, L., Bremova-Ertl, T., Cortina-Borja, M., Fineran, P., Morten, K., Poulton, J., Boland, B., Spencer, J., Strupp, M., Platt, F. M. Abstract: Acetyl-DL-leucine (ADLL) is a derivative of the branched chain amino acid leucine. In observational clinical studies ADLL improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder (LSD), Niemann-Pick disease type C 1 (NPC1). Here, we investigated ADLL and its enantiomers acetyl-L-leucine (ALL) and acetyl-D-leucine (ADL) in symptomatic Npc1-/- mice and observed an improvement in ataxia with both enantiomers and ADLL. When ADLL and ALL were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas ADL did not. These data are consistent with ALL being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were found to be implicated as one of the potential mechanisms of action of the L enantiomer in Npc1-/- mice. When miglustat and ADLL were used in combination significant synergy resulted. In agreement with these pre-clinical data, when NPC1 patients were evaluated after 12 months of ADLL treatment, rates of disease progression were slowed, with stabilisation or improvement in multiple neurological domains. A beneficial effect of ADLL on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in LSDs, supporting its further evaluation in clinical trials in lysosomal disorders. Copy rights belong to original authors. Visit the link for more info

A Purdue professor's invention is helping Parkinson's patients communicate, and a therapy in development in a Purdue lab could be a breakthrough for children stricken with Niemann-Pick disease type C, a rare, fatal disease.

A Purdue professor's invention is helping Parkinson's patients communicate, and a therapy in development in a Purdue lab could be a breakthrough for children stricken with Niemann-Pick disease type C, a rare, fatal disease.

This week, Ben and Andrew talk about Niemann-Pick's, Gaucher's, Fabry's, and Tay-Sach's disease. 

Niemann-Pick disease type C is a rare autosomal-recessive condition characterized by the accumulation of unesterified cholesterol in many tissues and storage of sphingolipids in liver and brain.

Niemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (lipids) inside of cells.

La enfermedad de Niemann-Pick tipo C es una condición rara autosómica recesiva caracterizada por la acumulación de colesterol no esterificado en muchos tejidos y el almacenamiento de esfingolípidos en el hígado y el cerebro.

La enfermedad de Niemann-Pick tipo C (NPC) es un raro trastorno genético progresivo caracterizado por una incapacidad del cuerpo para transportar el colesterol y otras sustancias grasas (lípidos) dentro de las células

Amalia Bruni, Lamezia Terme, Italy speaks on "Niemann-pick C: when diseases don't respect borders". This movie has been recorded at "Atypical dementias: from diagnosis to emerging therapies" conference.

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, and Kathy Spindler The TWiVirions reveal bacteriophage genes that control eukaryotic reproduction, and the biochemical basis for increased Ebolavirus glycoprotein activity during the recent outbreak.   Become a patron of TWiV! Links for this episode Nido2017 Meeting ASM Microbe 2017 Mark Buller obituary RS virus pipeline (pdf) Prophage WO genes and cytoplasmic incompatibility (Nature) Vanderbilt Virology (TWiV 332) Basis for increased Ebolavirus glycoprotein activity (Cell Host Micr) Letters read on TWiV 431 This episode is brought to you by Blue Apron. Blue Apron is the #1 fresh ingredient and recipe delivery service in the country. See what’s on the menu this week and get your first 3 meals free with your first purchase – WITH FREE SHIPPING – by going to blueapron.com/twiv Weekly Science Picks Rich - Germ Theory by Robert P. GaynesAlan - Student Scientist Partnerships Kathy - Symbiartic Dickson - PaleoBioDB Navigator Vincent - Kusama Infinity Room Listener Pick Chaim - How to fight back against the backfire effect Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Eye movements are important to aid vision, and they serve two main functions: to stabilize a moving visual target on the retina and to stabilize gaze during own body movements. Six types of eye movements have been evolved fulfilling this function: saccades, smooth pursuit, vestibulo-ocular reflex, optokinetic response, convergence and gaze holding. In all vertebrates the eyes are moved by six pairs of extraocular muscles that enable horizontal, vertical and rotatory eye movements. The motoneurons of these muscles are located in the oculomotor (nIII), trochlear (nIV) and abducens (nVI) nucleus in the brainstem. Motoneurons of the lateral rectus muscle (LR) in nVI and of the medial rectus muscle (MR) in nIII provide horizontal eye movements, those of inferior oblique (IO) and superior rectus muscle (SR) in nIII upward eye movements. Motoneurons of the superior oblique (SO) and the inferior rectus muscle (IR) in nIII convey downward eye movements. Recently, it was shown that each extraocular muscle is controlled by two motoneuronal groups: 1. Motoneurons of singly innervated muscle fibers (SIF) that lie within the boundaries of motonuclei providing a fast muscle contraction (twitch) and 2. motoneurons of multiply innervated muscle fibers (MIF) in the periphery of motonuclei providing a tonic muscle contraction (non-twitch). Tract-tracing studies indicate that both motoneuronal groups receive premotor inputs from different brainstem areas. A current hypothesis suggests that pathways controlling twitch motoneurons serve to generate eye movements, whereas the non-twitch system is involved in gaze holding. Lesions of inputs to the twitch motoneuron system may lead to supranuclear gaze palsies, whereas impairment of the non-twitch motoneuron system may result in gaze holding deficits, like nystagmus, or strabismus. Up to date only limited data are available about the histochemical characteristics including transmitters to the SIF- (twitch) and MIF (non-twitch) motoneurons. The present study was undertaken to investigate the histochemical profile of inputs to motoneuronal groups of individual eye muscles mediating horizontal and vertical eye movements including the inputs to MIF- and SIF motoneurons. The MIF motoneurons of the IR and MR are located in the periphery dorsolateral to nIII, close to the Edinger-Westphal nucleus (EW), which is known to contain preganglionic cholinergic neurons. Other scientists have found that the EW is composed of urocortin-positive neurons involved in food intake or stress. In order to delineate these different cell populations within the supraoculomotor area dorsal to nIII, a comparative study in different mammals was conducted to locate the cholinergic preganglionic neurons and urocortin-positive neurons. Only then, it became obvious that the cytoarchitecturally defined EW labels different cell populations in different species. In rat, ferret and human the cytoarchitecturally defined EW is composed of urocortin-positive neurons. Only in monkey the EW contains cholinergic preganglionic neurons, which lie close to the MIF-motoneurons of MR and IR in the C-group. In monkey, I performed a systematic study on the histochemical profile and transmitter inputs to the different motoneuron subgroups, including MIF- and SIF motoneurons. Brainstem sections containing prelabelled motoneurons were immunostained for the calcium-binding protein calretinin (CR), gamma-aminobutyric acid (GABA) or glutamate decarboxylase (GAD), glycine transporter 2, glycine receptor 1, and the vesicular glutamate transporters (vGlut) 1 and 2. The study on the histochemical profile of the motoneuron inputs revealed three main results: 1.The inhibitory control of SIF motoneurons for horizontal and vertical eye movements differs. Unlike previous studies in the primate a considerable GABAergic input was found to all SIF motoneuronal groups, but a glycinergic input was confined to motoneurons of the MR mediating horizontal eye movements. 2. The excitatory inputs to motoneurons for upgaze and downgaze differ in their histochemistry. A striking finding was that CR-positive nerve endings were confined to the motoneurons of muscles involved in upgaze, e.g. SR, IO and the levator palpebrae, which elevates the upper eyelid and acts in synchrony with the SR. Since double-immunoflourescence labelling with anti-GAD did not reveal any colocalization of GAD and CR, the CR-input to upgaze motoneurons is considered as excitatory. 3. The histochemistry of MIF- and SIF motoneurons differs only for vGlut1. Whereas SIF- and MIF motoneurons of individual eye muscles do not differ in their GABAergic, glycinergic and vGlut2 input, vGlut1 containing terminals were covering the supraoculomotor area and targeting only MR MIF motoneurons. It is reasonable to assume that the vGlut1 input affects the near response system in the supraoculomotor area, which houses the preganglionic neurons in the EW mediating pupillary constriction and accommodation and the MR MIF motoneurones involved in vergence. The histochemical data in monkey enabled the localization of the corresponding motoneuronal subgroups of individual eye muscles in human with the development of an updated nIII map. Taken together the present work provides new data on the histochemical properties of premotor inputs to motoneuronal groups of the twitch- and non-twitch eye muscle systems in primates. Especially the selective association of CR in premotor upgaze pathways may open the possibility for a targeted research of this system in human post-mortem studies of clinical cases with impairment of upward eye movements, such as progressive supranuclear palsy (PSP) or Niemann-Pick disease (NPC).

https://www.einstein.yu.edu - Determined to find a treatment for children with the degenerative brain disease Niemann-Pick Type C, Steven Walkley, D.V.M., Ph.D., turned a serendipitous laboratory discovery into a successful national research collaboration with other academic institutions and the National Center for Advancing Translational Sciences' program for rare diseases (Therapeutics for Rare and Neglected Diseases). These efforts led to an NIH Phase 1 clinical trial testing cyclodextrin as a therapy for children with this disease. Dr. Walkley is a professor in the Dominick P. Purpura Department of Neuroscience and director of the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center at Albert Einstein College of Medicine.

1) Niemann-Pick type C and 2) Topic of the month: Cerebellar ataxias. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Ted Burns interviews Dr. Matthis Synofzik about his paper on Niemann-Pick type C. Dr. Stacey Clardy is reading our e-Pearl of the week about cephalic tetanus. In the next part of the podcast Dr. Ted Burns interviews Drs. Susan Perlman and Jeremy Schmahmann about the topic of inherited ataxias. The participants had nothing to disclose except Drs Burns, Synofzik, Clardy, Perlman and Schmahmann.Dr. Burns serves as Podcast Editor for Neurology®; and has received research support for consulting activities with CSL Behring and Alexion Pharmaceuticals.Dr. Synofzik receives honoraria from Actelion Pharmaceuticals; receives travel funding from Movement Disorders Society and receives research support from the Volkswagen Foundation.Dr. Clardy served on the editorial team for the Neurology® Resident and Fellow Section. Dr. Perlman serves on Medical Research Advisory Board for the National Ataxia Foundation, receives research support from Santhera Pharmaceuticals, Edison Pharmaceuticals, Friedreich Ataxia Research Alliance, and ARRAS funding via the RDN-CRC.Dr. Schmahmann serves as an editorial board member for The Cerebellum; receives royalties from the publication of the books The cerebellum and cognition, MRI atlas of the human cerrellum and Fiber pathways of the brain; holds stock options in Brother and for legal counsel to Johnson & Johnson; receives research support from Birmingham Foundation MINDlink Foundation Sidney R. Baer Jr., Foundations and the NIH and has a patent pending for transcranial magnetic stimulation.

Guest: David Pearce, PhD Host: Bruce Bloom, DDS, JD How is the immune system involved in lysosomal storage disorders, including juvenile Batten disease, Niemann-Pick type C disease and Krabbe disease? Host Dr. Bruce Bloom welcomes Dr. David A. Pearce, director of the Sanford Children's Health Research Center in Sioux Falls, South Dakota, to discuss research into the immune response in these patients. Don't miss these other programs on MPS I, with host Dr. Bruce Bloom: Challenges in Management of MPS I Musculoskeletal Aspects of MPS I: Diagnosis and Management Considerations Long Term Efficacy and Safety of Laronidase for MPS I

Das 1914 als erstes durch Albert Niemann beschriebene, später als Niemann-Pick-Erkrankung bezeichnete Krankheitsbild, wird zu den Sphingomyelolipidosen gerechnet und umfasst eine seltene heterogene Gruppe von autosomal rezessiv vererbten Erkrankungen. Beim Typ A und B handelt es sich um eine familiär gehäufte, insbesondere in der jüdischen Bevölkerung auftretende Erkrankung, die durch einen auf Chromosom 11 liegenden Gendefekt, der eine vermin-derte ASMase-Aktivität zur Folge hat, bedingt ist. Die ASMase katalysiert den Abbau des Sphingomyelins zu Ceramid und Phosphocholin. Bei einem Mangel dieses Enzyms ist die Speicherung von Sphingomyelin im mononukleären Makrophagensytem vor allem im ZNS, der Milz, Leber und im Knochenmark charakteristisch. Beim Typ C und D dagegen liegt eine intrazelluläre Cholesterintransportstörung vor, die durch ein Fehlen des NPC1- bzw. NPC2-Proteins in den Endo- bzw. Lysosomen verursacht wird. Der Gendefekt, der zu einer NPC1-Erkrankung führt, ist auf Chromosom 18 lokalisiert. Da die ursächliche Störung des Typ D auch auf dem gleichen Chromosom liegt, handelt es sich beim Typ D um eine allelische Variante des NPC1. Der Gendefekt, der eine NPC2-Erkrankung bedingt, ist auf Chromosom 14 zu finden. Alle Subtypen sind durch die pathologische Anhäufung von Cholesterin und Sphingomyelin in den Lysosomen des ZNS, der Milz und der Leber, die in den meisten Fällen mit einer sekundär verminderten ASMase-Aktivität einhergeht, gekenn-zeichnet. Bei der Untersuchung von Patienten-Gewebezellen mit Verdacht auf Morbus Niemann-Pick sind wir in mehreren Schritten vorgegangen. Im ersten Schritt bestimmten wir die ASMase-Aktivität. Dazu verbesserten wir die in unserem Labor schon mit dem künstlichen Substrat HNP durchgeführte Aktivitätsbestimmung und führten zusätzlich eine radioisotopische Methode mit 14C-Sphingomyelin als Substrat ein. Mit beiden Methoden wurden die kinetischen Eigenschaften des Enzyms und der Aktivitätsbereich in verschiedenen Geweben und Zellen erarbeitet. Ein Vergleich der so ermittelten Aktivitäten in Patientenfibroblasten zeigte bei einem Typ-B-Patienten radioisotopisch eine Restaktivität von weniger als 10 % und spektrophoto-metrisch eine im Normbereich liegende Aktivität. Obwohl beide Methoden einfach und schnell durchführbar sind, ist die radioisotopische Methode der spektrophotometrischen vorzuziehen, um das Auftreten falsch negativer Resultate zu vermeiden. Dies ist durch das bei bestimmten Mutationen entstehende defekte Enzymprotein mit höherer Substrataffinität zum künstlichen Substrat und damit falsch hoher Enzymaktivität zu erklären. Von den in fünf NP-C-Patienten-fibroblasten bestimmten ASMase-Aktivitäten hatten vier eine partiell verminderte Aktivität. Eine sichere Diagnose der fünf NPC-Verdachtsfälle wurde durch eine Reihe von Verfahren, die wir erstmals in unserem Labor etablieren konnten, ermöglicht. Zunächst erfolgte der Nachweis einer Cholesterin-Akkumulation in den Lysosomen durch eine Immunfluoreszenzfärbung mit Filipin, einem Makrolid-Antibiotikum, das spezifisch 3β-Hydroxysterole bindet. Bei einem positiven Färberergebnis bestimmten wir die in vitro ASMase-Aktivität. Dazu wurde durch Kultivierung der Fibroblasten in cholesterinentzogenem (LPDS = - FBS) bzw. reichem (+ FBS) Medium eine Cholesterin-Akkumulation simuliert. Mit dieser Methode ist aufgrund der charakteristischen sekundär verminderten ASMase-Aktivtät in NP-C-Zellen nach Bebrütung in cholesterinreichem Medium eine sehr sensitive und spezifische Diagnose pathologischer Zellen möglich. Eine phänotypische Klassifikation der NP-C-Zellen erforderte die Durchführung der Oleat-Inkorporationsmethode. Es gelang uns drei Patienten mit klassischem und zwei mit einem varianten Phänotyp zu diagnostizieren. Als Letztes bestimmten wir die zytoplasmatische CEHase-Aktivität in NPD- und Kontrollfibroblasten im leicht alkalischen Bereich. Erstaunlicherweise lieferte diese Messung eine verminderte Aktivität in drei NP-C-Fibroblasten, die bisher in der Literatur nicht beschrieben wurde. Es ist auch keine Erkrankung mit diesem Enzymmangel bekannt. Deshalb nehmen wir an, dass zusätzlich zu den Mutationen der NPC-Proteine bei manchen Patienten eine weitere Mutation entweder auf Chromosom 18 bzw. 14 oder in einem bisher noch nicht identifizierten Gen liegen muss. Durch die Etablierung dieser empfindlichen Methoden zur Bestimmung der ASMase-Aktivität und zum Nachweis einer intrazellulären Cholesterintransportstörung war es uns möglich, erstmals in unserem Labor zehn Patienten mit Niemann-Pick Erkrankung, davon zwei Typ A, drei Typ B und fünf Typ C, mit großer Sicherheit zu diagnostizieren. Unsere Untersuchungsverfah-ren erwiesen sich als mit verhältnismäßig geringem Aufwand durchführbar und günstiger als die bisher durchgeführten Methoden. Zur Diagnosestellung reicht eine Hautbiopsie in den meisten Fällen aus, so dass den kleinen Patienten eine invasive Diagnostik erspart werden kann.