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#188 Propionic and Methylmalonic Acidemia with HemoShear Therapeutics

by Kira Dineen
June 10th 2022

Propionic and Methylmalonic Acidemia (PA and MMA), including an investigational therapy, are explored in this episode. Host Kira Dineen is joined by patient a... More

you're listening to a podcast and radio show where we discover new advances in the world of genetics from genetic technology like CRISPR to rare diseases to new research. We have you covered for a decade, DNA today has brought you the voices of leaders in genetics. I'm tired. I mean I'm a certified genetic counselor and your host. Perkinelmer genomics is a global leader in genetic testing, focusing on rare diseases, inherited disorders, newborn screening and hereditary cancer testing services support the full continuum of care from preconception and prenatal to neonatal pediatric and adult testing options include sequencing for targeted genes, multiple genes, the whole x. Um our genome and copy number variations using a simple saliva blood sample. Perkinelmer genomics answers complex genetic questions that can proactively inform patient care and end the diagnostic odyssey for families, learn more at perkinelmer genomics dot com. In this episode we are going to be exploring not one but two genetic metabolic disorders.

Joining me for this discussion is brian and Pat brian kelly is 35 years old and is living with probiotic academia. He's a great inspiration to parents, patients. Caregivers like finding ways to live a fulfilling life despite the burdens of his disease, brian needs his yoga and meditation techniques for pain relief and is active on social media. So we're gonna be plugging all of that during the episode. And he regularly reaches out to the p a community through social media dr Pat Horn is the chief medical officer of him, a shear therapeutics. His company is developing a potential new treatment for the two rare metabolic diseases that we are talking about in the episode. So, pro bionic Asadi mia and meth a moronic acid e mia. He has practiced for 20 years as a pediatrician and has spent the last two decades working with biotechnology companies developing new treatments for rare diseases. So, thank you both so much for coming on the show. I think it's so great to be able to hear from both of your perspectives. Well, thanks for having us. Thank you. So brian, I would love to kick off our conversation talking about the start for you in terms of how you were originally diagnosed with probiotic asada miA, which I think we're going to end up saying p a lot during the interview for people.

So I was actually a very really diet notice on late, I was really sick as a baby, but the doctor didn't know why. Um and then my mom kept telling telling them all, he said, he said and the doctor said I was just a sweetie baby And then I ended up having uh another about two and I was in a coma for what that is. And that's kind of how so that must have been very scary for your parents, I imagine to have little baby in a coma for four days. Yeah, certainly. And and so you know, that was when you were first diagnosed as a baby, you know, moving through our timeline a little bit. What was your childhood like with the disease? I think, you know, compared to other kids that you were growing up with. So my childhood, um, I was I was in and out of the hospital a lot, I would say until about the around seven, I guess that's when I kinda start getting a little bit bigger.

But I was I had a lot of seasons young, a lot of high ammonia flap because I still have today sometimes spent a good portion of my life on my childhood in the in the possible. And that's really hard to keep up with school and activities when you're spending so much time in the hospital. It's certainly not the place you want to be as a kid, Right. And how did your parents help you manage this? I imagine that they were a big part of being advocates for you and helping you in the hospital talking about doctors. Oh, absolutely. My parents were funny every step of the way. I was never supposed to walk or talk and they got a simple Yeah, definitely. I mean, I think for so many people with genetic conditions, it's so important to have early intervention in terms of having that help of, like you said, physical therapy, speech therapy, I think that's something that a lot of people with genetic disorders have in common of having those support systems in place.

Um, and as you said, you know, you're, you know, functioning well today and enjoying life, which we'll talk about some hobbies that, you know, you're interested in. Um how has P A affected your health and activities now as an adult, I think, you know, you're 35 right? So little little older than me. Yeah. 36. I am behind you had a birthday happy belated. But as far as today, um, I would say due to the P. A. I have uh the rackets to violence is a big issue for me that can't do. Uh I can't lift about 30 lb. Oh, and because that's the basis, um, I just have a coil biographies. I get tired of word quickly. Um, also my fine motor skills are kind of off. So I have a hard time like things like that, some things that you adapt in your life as opposed to someone else that you're friends with that's also you know, your age.

Um, so just doing things maybe a little bit differently than a typical person. So that, so I know you're involved in meditation, which I think is really cool. You know, I don't know, you know too much about it in terms of using it on a regular basis. I mean, how has this helped you cope with some of these symptoms that you've been talking about? So I ended up getting in 2012 and how that affected with them. Probably honest, we will never know. Um, but I, I started getting high among the flaps and I've gone to all kinds of dogs, but including in texas disease and my probably on the doctors and no one can actually tell me these solutions as to why they keep happening because they come and go, I say get one like once a month and it lasted about, oh, it so I use meditation to be become mindful and kind of recognize that when I'm not feeling good, I just need to sit down and relax, take it easy.

Yeah, I think that's so important and there's such a bond between our physical health and our mental health. So I think, you know, you're bringing up a very good point with that of being in tune with yourself and having your, your body being able to communicate with your mind and your mental health there. Exactly. Also, you know, the more we focus on tame and the these, the more we create it. So yeah, that's a that's a really good quote. I think of being able to distract yourself is often something like even with kids, right? When we have a kid, like stub their toe or something like, you know, we're like, okay, like we're gonna kiss it all better. Like a part of it is a little mental, right? When we're like, ok, we're giving you a solution, you put abandoned on a kid is suddenly so much better, right? So I think there is that connection there. Exactly what are some other things that you've learned through, also yoga that you're involved in with yoga and your mindfulness journey. Yeah, so I found yoga before I found meditation and I started when I was diagnosed with the Lion, I I kick boxing and kickboxing became too much money and too hard.

It gets very expensive. I started doing boxing and I'm like, wow, this is a lot of money. I think the treadmill would be cheaper. I found yoga with Adrienne Youtube, who is one of the biggest senses that you're about now. Um and I just started building her videos, fell in love of that and then one thing led to another and now now I'm actually taking a yoga class, wow, very cool. And you've been sharing a lot of this with the P. A community in terms of helping other people with mindfulness. Can you tell me a little bit about that and who you've connected within the community just in terms of, you know, if it's caregivers, if it's patience if it's a little bit of everybody. Yeah, so I give I give 11-11 meditations every Saturday. Um they run about 10 minutes long. It's a great way to kind of let go of whatever is going on in the day, so for far and in life dental, just to focus on something else.

Um and you know, it's it's great for the p a kind of, you know, they're under a lot of stress and stuff. It's also good for anyone who has mental health or anxiety or anyone in general really. I think we all have our own levels of anxiety, I think some more than others, and I think that that's something that's universal in terms of, you know, grounding yourself and using a lot of breathing techniques and some of that with yoga at the same time um can be really helpful. Last weekend, I was at a camp for kids and we were doing some of that with the kids and so it was it was it was really great even as I was doing it, I was like, wow, I can notice like, you know, I feel lighter, I feel looser. Um So it's it's such a it's such a great activity to do, to really, you know, find with yourself almost as we kind of are about to turn over to dr Horn. Do you have any advice for people with P. A caregivers of people with P. A. In terms of just having experience of living with the condition, experiencing, living with, I would say try not to that's out over it too much and, you know, kind of just focus on what you can control.

I think that's really good advice and just um there's a Maya Angelou quote that I like thinking of is if you don't like something change it, if you can't change it, change your attitude and I think that really speaks to what you're saying. Yeah, I've always loved that quote. I'm like that is that is something to live by. Maya Angelou has a lot of good good quotes out there. But anything that you're hopeful about, anything that you have been focusing on, any goals that you've had recently right now I'm just focusing on my spiritual path teaching myself today and nice. Amazing. Well thank you so much for just sharing so much of your experience. And we were talking a little bit before we started recording that you have this awesome website Be present lifestyle dot com. So people should definitely check that out. And it's also in the show notes. Did you know Perkinelmer genomics was one of the first laboratories to offer whole genome sequencing on a clinical basis. Whole genome sequencing can maximize clinical diagnostic yield for patients with turnaround time of four weeks for the pro band sample.

Perkin Elmer's whole genome sequencing test is designed to provide access to additional valuable information compared to an Exxon Perkinelmer also offers prenatal whole genome sequencing as well as ultra rapid whole genome sequencing for critically ill newborns Using dried blood spots. The ultra rapid genome has turned around time of five days and includes mido chromosome O. C. And D. Analysis str TnR screening and biochemical analysis. Also listen back to episode 1 76 with Dr Madhuri Hegde where we explore the power of whole genome sequencing which also happens to be one of my favorite episodes DNA. Today and stay tuned for a couple more episodes of perkinelmer soon discover all the perkinelmer genomics has to offer at perkinelmer genomics dot com. So Pat, I'd love to loop you into our conversation um and dive more into like the genetics and science side. Um so as brian and I have been talking pro bionic and metal melodic Asadi mia or metabolic disorders.

So how do these conditions affect the body? Like what symptoms do people generally have? And do most people have like brian's experience of being diagnosed as a baby? You're exactly right. These are both genetic diseases. They both fall under the category of inborn errors of metabolism. Um And and they are conditions in which, you know when you consume proteins when you consume fats and the body breaks them down for energy. There's multiple steps in that process. And their enzymes that mediate each of those appropriate nick academia and meth a melodic academia are different in that they affect different enzymes but they're all part of the same pathway. And because these enzymes aren't working quite right. There's a build up of toxic intermediate and toxic metabolites and these then poison the mitochondria and you can't produce as much energy and and they cause metabolic crises. I would say that most patients are diagnosed in infancy now and it's either the majority of them because they get sick very quickly because when they start to breastfeed or in formula they're taking in proteins.

the body breaks down these proteins and they get into a metabolic crisis. Um And and many of them are are diagnosed within the first few days of life. Some are not. But every state in the in the U. S. Now has ah the newborn screen screens from meth a melodic acid e. Mia and appropriate nick Cassidy mia so that sometimes the newborn screen comes back positive and then pediatricians and health care reach out to the families and that starts the process. So I would say in the United States, specifically, almost everyone is diagnosed early in infancy. And is that something that's a recent change in terms of having it on newborn screening for every state because it's state dependent, but there's some conditions that it's every state has. But um I know like Connecticut's estate that tends to have more conditions than others. Um And I've always wondered if that's because nord has an office here, national organization for rare disorders. But is that a recent change? Has that been the case for decades? So, No, it's a recent change, you know, with the newborn screening a lot of it And I can't tell you whether it's been the last decade or the last 15 years, but it is it's relatively new and to have it and and obviously some states like you said have started screening much earlier and some it's a relatively recent addition and because of that, I imagine virtually all babies that are born in the US are then going to be caught with the newborn screening.

Um Do you need a official like diagnosis after that with additional testing to say okay, yes, because you've had screening to say, okay, this baby has a higher chance for having one of these conditions. And then do you need like a test to confirm or at that point that's all you need is the screening? Well, so you know, yes, you do need a confirmatory test is the short answer because you know, with any of these there are false negatives or false positives with in this case would be more interested in a false positive. Um So sometimes depending on how sick the child is, you know, oftentimes these babies are sick by the time the newborn screen comes back and but then there are the ones that are doing better than you can repeat the newborn screen. I think in the US today, almost everyone has a genetic test to confirm the diagnosis and and confirm the genetic variant that it is. Um That's not not so much in the rest of the world.

But I would say in the US, almost everyone is gonna have a genetic test. There are other ways to diagnose it, you know, by doing the metabolite levels, looking at the metabolite levels in the blood in the urine and then maybe even doing some enzyme assays. Um But for now it's mostly genetic analysis and when we are looking at some of the information about these conditions P. A. And M. M. A. What is the prognosis and lifespan for someone that is diagnosed? I imagine that's also changed over the years. Well so for a like a lot of genetic conditions there's a big variability in how severe it is and that's because there are a number of different variants and they all impact the enzymes differently, you know. So some so those variants that lead to like a complete absence of enzyme function or You know, reduce it by 90 Have a much more severe disease than those that reduce it by 20% or 30%.

And and so individually it it can be very different uh in terms of prognosis many of these of these Children um will be very sick early on and then they tend to outgrow their hospitalizations as so much some do some don't. But then there are a lot of kind of long term complications from the even the lower levels of the metabolites in terms of how patients do. You know, there are patients like brian who live independently have a you know a very ah good life in in in that and some are more severely affected and and won't be independent and developed in very progressed renal disease and in cardiac disease, you know the reality is it probably hasn't changed much in the last few decades. There's no specific therapies yet and there's there's none of that and and recognizing that need is is kind of what what he mushier is has really tried to do. Yeah, certainly because you have a drug that you're currently in investigational therapy, I should say that's in development.

What's the goal of this therapy? I mean, you're saying that there's sounds like there's not great treatment options right now. So you're looking to change that? Right? So, so yes, so our compound that we're looking at is one called HST 50 40. Uh and as you said, it's an investigational product that's not approved in any country in any place. So it really is just an investigational product that, you know, it's restricted to clinical trials right now. Um but in the lab, you know, in cultured parasites from patients who had had M. A. M. E. R. Method. Melodic Academia appropriate nick, Cassidy mia and had undergone liver transplant and we've taken those and can grow those cells under special conditions that mimic the disease. H. S. T 50 40 decreases the levels of these, what are called the toxic metabolites. So the metabolites that build up as a result of the enzyme blockade. HST 50 40 in the cell systems reduces those two very low or near normal levels.

So it like neutralizes the toxic substance that's building up that's causing the symptoms. Yes. So it gets rid of those toxins. Um, you know, and the hope is we will see the same thing as we move into a clinic population and into patients. So that's what the clinical study is designed to do. Um This is the first time this drug has been given to patients with appropriate Cassidy me in math Melodic academia. So we're looking to see does it actually work? Does it do the same thing in people that it does in the lab? And is it safe? What is the safety profile of this drug? And that's the aim of the of the study that's called the hero study? And so how does this differ from treatments that are currently available? Like what the standard of care would be for someone that has P. A. Or M. M. A. I mean, how much do those treatments truly alleviate symptoms? Because it sounds like the the investigational therapy that you have, like we could really be onto something in terms of eliminating a lot of the symptoms if those toxic levels are brought down.

So what is that compared to what's on the market today? Well, so really the standard of care right now is primarily diet therapy. So uh the patients are put on diets that really restrict certain proteins. You know? So proteins are built up of amino acids when your body breaks the proteins down for energy, it breaks them down and there's a group called the branch chain amino acids. Then they go into this pathway that's affected by method, melodic as sodomy and appropriate nick, Cassidy mia. So the goal of diet therapy is to reduce the exposure to those specifically branch chain amino acids uh and and supplement them with amino acids and with different food sources. A lot of carbohydrates that the body can uh that can metabolize without the build up of these products. Um There really is no specific drug therapy for this uh You know, patients um are are supplemented with vitamin B and in some patients that helps the different enzymes, you know, depending on the different variants of the genetic mutation, but vitamin supplementation, carnitine supplementation to help kind of control all that.

Those are the primary ones. More and more now patients are undergoing liver transplantation to ah ah as a treatment for these. And what liver transplant does is it does reduce um the the fluctuations in these metabolites, especially the very very high fluctuations, the ones that are called metabolic decompensation and and lead to hospitalizations. But patients can have ongoing problems as a complication of of not being able to fully normalize the levels. So this, you know, so there really are no specific therapies, drug therapies targeted for these diseases and these conditions yet. So it's a lot of diet control so that you're trying to eliminate eating the substances that the body has a hard time breaking down properly if I'm getting right right. Yeah. Taking me back to like, you know, the metabolic class I took in grad school and everything and it's like, that was definitely one of the harder classes I'll say.

So, you know, you have a tough job, you know, and continue to provide these patients with all of the energy they need to grow and develop as normally as possible. And so that's where that's where it balance and and again, then even, you know, even if their diet is well controlled and that's working when when people get sick or they have a fever, even just a cold, then there's a big energy requirement and your body actually starts to break down its own protein. So what happens when when these Children and these patients start to get sick is they take on a lot more energy in terms of carbohydrates and stuff. So, to provide energy for your body without breaking down the proteins. Some patients can can manage very well with that. Some patients, even with all the diet restrictions, the ones that are on the more severe in continue to have problems. Yes, it's certainly a wide range like we see with many genetic disorders. Um, and it is interesting, I feel like as we, you know, advance more with our technology and understanding of genetics, it's going to become more and more important to know what variant someone has that is genetically causing this disorder because that's where personalized medicine is going to come into play of just even knowing, you know, maybe for someone with one of these disorders, the treatment won't change necessarily, but that the prognosis might change if knowing like, okay, you've got mutation A versus B.

A. Has, you know, the enzyme barely works, whereas B. It works fairly well, but not as good as someone that doesn't have a disorder and just knowing like that one of them is going to be more affected than the other. I mean, maybe this is already very much into play and I'm just not aware. Um but it seems like it's becoming more important to know variants and and that's becoming incredibly important in a lot of genetic conditions. Not a lot of literature out there yet in mathematic academia appropriate nick academia to look at that they're starting to be some. Um but but not a lot. And is that at all part of the hero study of looking at what variants people have or is that maybe a future study? So, as as part of the hero study, you know, we are collecting the variance and trying to look at that. Um And and so, but that's gonna be A longer term thing. You know, the hero study is relatively small study. You know, we're looking to recruit 12 patients. Um those kind of analysis really take much larger cohorts, so more like a natural history type study or as as people continue to develop potential new therapies in these diseases and collect that across the different, different therapeutic modalities to try to bring that in and get enough data to really draw some meaningful conclusions.

Yes, certainly. I think cystic fibrosis is a great example of that. We know a lot of the different variants and what that can mean in terms of the symptoms a person may have and what medications they're going to be taking. Um so I think that's kind of one that has been like a poster child in terms of like, okay, what could we be looking at for other genetic conditions down the road? So if people are listening and either they know someone that has P. A. Or M. M. A. Or they have it themselves, they have patients with these conditions. What is the inclusion criteria or what is needed for someone to be eligible to enroll in the hero study and possibly be one of these 12 people. Okay, so so you need to have, you know, to get started, you need to have at least a clinical diagnosis of either method, moronic acid, a more appropriate nick academia as part of the study screaming process. If you have not yet had a genetic analysis, will do the genetic analysis to make sure that that that's in fact what you have. I think that's it and and patients and and need to have a history of having at least one hospitalization for what's called the metabolic decompensation.

Um And right now we're enrolling patients two years and above. So any age above two years, they're eligible. As long as they have the diagnosis and and then also to have some high metabolite levels. Method, melodic asset and nmC A levels. Okay, so let's see if I've got it. So they have to have a a a clinical diagnosis which if they don't have a genetic one, you could confirm that um they need to have been hospitalized with a crisis of some kind um related to it. Um and be above the age of two. Did I miss one was their fourth? Well and and they need to have elevated metabolite levels elevated. Oh my goodness, elevated metabolic levels, metabolite levels. Okay. Alright, so I think we've got that. Um Well, I mean, thank you so much for sharing so much information with this. Um People can head over to him, Osher dot com. That's H E M O S H E A R dot com.

Um And what we were talking about with brian earlier, you can head over to be present lifestyle dot com. We're gonna have all the links in the show notes for you. Um So really you can remember D. N. A podcast dot com. Just head over there. But thank you so much both for coming on and sharing your expertise and your experiences. I think it's just so valuable for people to hear from both of you. I think it's just great when we can have a patient advocate on and someone that's working in the field. Um, so thank you so much brian and Pat. I just appreciate it so much. Well you're welcome and and again thank you for the opportunity and for DNA today listeners tune in next week. We're going to be talking with, you know, tips actually for the next two weeks. So we've got rate two episodes coming up to celebrate pride month. So you're not going to want to miss those for more information about today's episode visit DNA podcast dot com where you can also stream all episodes of the show. We encourage your questions, comments, guest pitches and ideas.

Send them all into info at D. N. A podcast dot com. Search DNA today on twitter, instagram youtube facebook so you can connect with us there and a favor. Please rate and review the podcast on apple Spotify or wherever you listen. This truly helps us climb the charts and allow more genetic nerds like yourself to find the show. DNA today is hosted and produced by myself here Deneen, our social media lead is korean Merlino. Our video lead is Amanda and really thanks for listening and join us next time to discover new advances in the world of genetics. The genes of you and me and they're all made of D. N. A. We're all made of the same

#188 Propionic and Methylmalonic Acidemia with HemoShear Therapeutics
#188 Propionic and Methylmalonic Acidemia with HemoShear Therapeutics
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