Intro: Welcome to Pediatric Voices, Duke Children's podcast about kids health care. Now here's our host, Dr. Angelo Milazzo.

Dr. Angelo Milazzo (Host): Hello and welcome to Pediatric Voices, a podcast that dives deeply into conversation with the people who make up the Duke Children's healthcare team. I'm Dr. Angelo Milazzo, a pediatric cardiologist and Professor of Pediatrics at Duke Children's and a co-host of the podcast. I'm here to bring you expert insights about timely topics in children's health.

On this episode of Pediatric Voices, let's look at the early diagnosis and treatment of genetic diseases in children. The field of genetics is one which has exploded across the public consciousness in the last several years. It seems as though everyday media outlets are including headlines about amazing genetic advances and innovations, and these are being noted regularly in the news cycle. Things like CRISPR and genetically-modified crops and genetically-modified organisms, et cetera. We're hearing about exciting advances now, both in the treatment and even the possible cure of diseases that were long thought to be uncontrollable and incurable.

Many of these genetic diseases have devastating consequences for patients and families because they begin to have an impact at the earliest stages of life and have significant consequences for growth, for development and for life expectancy. So, the possibility of being able to diagnose these conditions early and early enough to have a real impact and offer really substantial treatment for these patients may seem more like science fiction than science fact, but here we are.

I'm very fortunate to have the ideal guest to help us sort through this topic today. I'll be talking with Dr. Jennifer Cohen. Dr. Cohen is a medical geneticist, which means that she has completed training both in pediatrics as well as in the specialty field of genetics and metabolism. She's an assistant Professor of Pediatrics in the Duke University School of Medicine here in sunny and very warm Durham, North Carolina.

Dr. Cohen joined our faculty in 2019 after training at the Children's Hospital of Philadelphia, which is a preeminent children's hospital here in the US. Her research interests and her clinical expertise are in perinatal genetic medicine, which focuses on the early diagnosis and management of rare genetic diseases. She's also working on the problem of rapid and comprehensive testing for critically ill neonates who may have genetic diseases.

I'd also like to note that she recently published an important article in the New England Journal of Medicine regarding the first child treated for a rare genetic disease called Pompe disease treated before birth, which obviously is a very exciting development in that work. So welcome, Dr. Cohen. Jennifer, it's a tremendous pleasure to have you here on Pediatric Voices.

Dr. Jennifer Cohen: Thank you so much for having me. I'm excited to talk about this topic today.

Host: Oh, that's wonderful. You know, I always like to start out these conversations getting to my guest's origin story. So tell me, how did you first get interested and involved in children's health?

Dr. Jennifer Cohen: Absolutely. So, I actually came to it through a more circuitous route, I would say. In medical school, I was really interested in my embryology course and decided to pursue some summer research in maternal-fetal medicine with the maternal-fetal medicine doctors at Mount Sinai where I was training and I really loved maternal-fetal medicine and had thought for many years that that would be the path that I would pursue.

I took a year out though between third and fourth year of medical school to pursue a cardiovascular research fellowship at the University of Pennsylvania. And during that time, I was across the street from the Children's Hospital of Philadelphia and began to think a little bit more about my love of embryology and how that might tie in maybe more toward pediatrics and children's health. So, I started shadowing a pediatric endocrinologist actually at Children's Hospital of Philadelphia. And during that year of research, I really came to love pediatrics and started thinking about how I could combine my interests in research and embryology and medical care. And that's what really led me to the field of medical genetics.

And at that point, I decided I wanted to pursue a dual career in pediatrics and medical genetics, and eventually applied for a combined residency at the Children's Hospital of Philadelphia, where I pursued my postgraduate training. And that's where I really fell in love with children's health, was right there at CHOP from the beginning.

Host: I think it's fascinating that embryology was one of those courses, one of those early experiences that inspired you. I can say that as a pediatric cardiologist, that's very common in my field as well because we deal with things that are directly connected to embryology. And that was my experience as well. Embryology was one of those classes in med school that really I think began me on the road toward becoming a cardiologist. So I, again, I think that's really interesting.

So Jennifer, thank you for giving us your perspective and your background and how you got interested in caring for children. I now want to get your overall perspective on today's subject, the subject of genetic diseases and particularly, because it relates to your interest, the importance of early diagnosis and treatment. So, can you give us the overview of the subject and perspective that we ought to be focusing on in our discussion today.

Dr. Jennifer Cohen: Absolutely. So, genetic diseases don't just affect children. We know they affect adults and adolescents, of course, as well. My focus in my career and my research has really been on those diseases that start in utero and continue on through childhood, so the diseases that there is something going on very early on from a physiologic perspective. And that might be a missing enzyme in a person that's due to a gene that has been mutated or it can be a congenital anomaly. And those are things that occur very early on, like we talked about with embryology, or something that there is a gene that's not working and leads to a deficiency of some kind from a metabolism perspective or a genetic perspective.

And so, my feeling is for those diseases that we know occur very early on. If we can diagnose them at a really early stage before the symptoms really take hold, we can maybe intervene early enough to prevent symptoms instead of trying to play catch up and trying to rescue the symptoms after they've already taken hold. So with that, I pursued a lot of research in residency and now as faculty in how can we diagnose earlier and how can we treat earlier. And so, my most recent work and the work that I've been working on for the last four years or so in a collaboration with the University of California San Francisco is a phase I clinical trial to treat in utero eight different lysosomal storage diseases, which is a subset of the many different genetic conditions that can occur in children. This is a small subset known as lysosomal storage diseases. And we've been focusing on eight of those diseases that have really early onset and have available enzyme treatments. So, these are conditions where the enzyme is not working or is deficient in a patient. And if we can replace that enzyme really early on, we can hopefully prevent the symptoms from taking hold and developing in the first place.

Host: So, let me make something clear for our audience. When you say in utero, you're talking about treating a baby while his or her mother is still pregnant.

Dr. Jennifer Cohen: Yes. Thank you for clarifying that. Yes. So in utero, I mean, we are giving that enzyme that would normally be given to a baby, a child or an adult via the peripheral blood, essentially a vein. Instead of going through a vein in a child or an adult, we are actually delivering that same enzyme through the umbilical cord vein while the mother is pregnant. So through ultrasound guidance, similar to how other procedures are done, similar to how you know, blood transfusions might need to be done if a fetus is anemic, very similar procedure, but instead of giving blood, we're giving this enzyme through the umbilical cord vein and hoping to prevent the symptoms that develop as a result of the genetic condition.

Host: So, how then would you identify your patient? So, is it through some screening during the pregnancy? Is it through knowing that a particular family may have a disease that has appeared in several generations? How do you know who needs to be treated?

Dr. Jennifer Cohen: That's a great question. So, for the most part right now, the patients that are coming to us, especially for this phase I clinical trial, are families that know they are at risk of having a child with this disease. So, that might be two parents who have had children in the past, so siblings of the current fetus that were affected with the disease. And that kind of clued them in to know that they might be unaffected carriers themselves, the parents, of this disease. A lot of the diseases we're treating are inherited conditions, meaning they're either inherited from two unaffected parents or potentially one unaffected parent, depending on the inheritance pattern of the condition, and that sort of clues them into knowing, "Okay, we have a family history. We know our next child is at a certain percentage risk of being affected." After that, the pregnancy can be tested through certain screening procedures or diagnostic procedures, namely chorionic villus sampling and an amniocentesis. Those are diagnostic tests where we can confirm whether or not a child is affected with that family history of disease.

The hope really though, of course, is that we would capture the very first patient in a family and not have to wait for a sibling to be affected and potentially have devastating consequences of that disease. So, the hope really is that preconception carrier screening, which basically looks at parents who are getting ready to conceive or maybe have just conceived a pregnancy, to know what their risk of inherited diseases is and test the pregnancy for those conditions for which they are both carriers for or in which someone is a carrier for that would cause disease.

So, that's the end goal really, I would say, is to expand universal preconception carrier screening and not have to wait for a devastating illness in a child, but to actually capture the very first child in a family and intervene early on to help them and potentially future siblings as well.

Host: Jennifer, your answer raises a question. And it's interesting, I recently had Dr. Andrew Landstrom on the show, and we talked about cardiovascular genetics, of course, because that's his specialty, and we talked about screening, particularly home screening. You know, it's become very popular for people to order these readily available test kits. They're very inexpensive, they get results very rapidly. But often I think when they get results, they are not sure what to do with those results. Are you saying that it may be possible for families to identify risk through testing such as those home tests as well? Or would you say that that's not the correct route that families should choose if they suspect that there may be a problem in their family?

Dr. Jennifer Cohen: So direct-to-consumer testing, which is what you're describing, is not what is recommended to determine risk of genetic disease. That sort of testing might be fun and useful for figuring out ancestry, background and doing some kind of fun genetics, I would say. But if you're really looking for genetic disease risk, either in yourself or your future children, the best route to go is through a commercial genetic laboratory that is specifically looking at genetic disease risk and has the capabilities to look at what we call pathogenic variants or disease-causing variants, also known as mutations, and really identifying those variants in a very structured way with a lot of regulations and a lot of oversight.

And so, what we would recommend if someone is interested in any sort of genetic testing for disease risk or for disease, if they are affected with symptoms, of course, would be to see a geneticist, which is a medical geneticist like myself, alongside a genetic counselor. Sometimes genetic counselors practice even independently for these sorts of things, especially for preconception genetic carrier screening. That can be done through an obstetrician's office in conjunction with a genetic counselor, for instance. But really, we recommend seeing a medical professional in the field of genetics when you want to pursue genetic testing for disease risk specifically.

Host: So, it sounds like that would be the first place to start, is to seek out a professional, either seek out a medical geneticist directly or perhaps a pregnant woman could reach out through her OB-GYN or her perinatal specialist, perhaps even her pediatrician, if she has no other easy avenues to explore. But it boils down to the fact that there are multiple ways to get help and that you really do need to seek the advice of a professional.

Dr. Jennifer Cohen: Absolutely. I would 100% agree with that, and a pediatrician can definitely get that process started, either by making a referral to a medical geneticist or putting you in contact with someone that can specialize in that field and help.

Host: Let's talk a little bit about this treatment itself, because it sounds amazing. You're talking about providing a treatment at the earliest stages of life. What are the risks, both to the fetus, to the mother, if there are any? What are the benefits?

Dr. Jennifer Cohen: Sure. So, the main risk really with any fetal intervention is going to be inducing preterm delivery or preterm labor. So, that's really the highest risk. Of course, there's always risk when you're intervening for infection or things of that nature. Of course, it's done under a sterile environment, a sterile condition, but the biggest risk really is concern for preterm labor and delivery.

So, that's the risk there and it is a risk that I would say is seen in any fetal intervention, not specific to this fetal intervention. The benefits that we've seen so far from the patients we've treated in this trial is that we see the prevention of the symptoms that would normally be seen even in utero, prenatal life and, certainly, in early postnatal life after birth. We've seen the prevention of that.

And a perfect example is, since you're a cardiologist, I'll discuss the heart, because in infantile Pompe disease, the heart is affected. There's a thickening of the heart, and this can occur as early as the third trimester of pregnancy, and we see it on a fetal echocardiogram as early as 34 weeks, let's say. And what we saw with our patient that we treated prenatally starting at 24 weeks, in that patient, we saw that she never developed cardiac hypertrophy. And this was very unlike her sibling who developed cardiac hypertrophy that was fairly significant by the 34-week fetal echocardiogram and had progressed by the time of birth. And our patient who is now over two years old has never had a day of cardiac hypertrophy in her life, which is a really wonderful thing for this family and for the patient, of course.

Host: It is wonderful and it is amazing. And again, it sounds more like science fiction than science fact. It's absolutely incredible. Would you then consider that patient cured or will that patient need continued treatment and surveillance? What does the future look like for a patient like this?

Dr. Jennifer Cohen: That's a great question and a really important distinction between treatment versus cure. And I think because this patient will continue to need her enzyme replacement therapy-- that's what the medication is known as when we give back this enzyme that's not made by the patient herself-- she'll need that enzyme replacement therapy every week for the foreseeable future until there is a cure for this condition. So really, she is treated but not cured. The hope, however, of course, is that in her lifetime, we will see cures. And there are many developments, especially in the field of lysosomal storage disease, which this is one example for gene therapy. And that's another aspect of research that I work on here at Duke, is gene therapy for lysosomal storage disease, including for Pompe disease. And the hope, of course, is that we will see gene therapy be successful in her lifetime, and that would ideally, we hope, provide a cure for this condition.

Host: Jennifer, I think people are hearing about gene therapy in the context of other diseases, too. Of course, you and I deal with things like lysosomal storage disease and Pompe disease. They feel familiar to us. I think to many people, they seem incredibly esoteric and rare. But most people know about genetic diseases like sickle cell disease or cystic fibrosis. Are those diseases also In the batting order, so to speak, to be eventually treated genetically with targeted therapy or with gene therapy? What can you tell us about those diseases?

Dr. Jennifer Cohen: Definitely. So, I think any condition that is what we call monogenic or single-gene disease is a candidate, I would say, for gene therapy or gene-targeted therapy. So, sickle cell disease and cystic fibrosis are perfect examples of single-gene diseases. Basically, that means that one disease is caused by one gene. There can be multiple genes that cause a disease, but one gene at a time causes the disease. This is in contrast to something that we would consider to be a polygenic disorder. That might be something like high blood pressure or diabetes, where we think that genetics definitely plays a role in these conditions, but it's not the only player in those conditions. And it's probably not one single gene acting alone that's causing these conditions. And that's in contrast to the monogenic single-gene diseases that we're talking about today, where I think gene therapy is definitely going to be that next phase of research, and it is ongoing already for many of the diseases that you mentioned that will kind of take us to that next level and hopefully eventually to cures for these conditions.

Host: Again, it's amazing to think of these diseases as being potentially curable where for so long, we've kind of struggled with just being able to treat them adequately. Treatments, of course, have improved for most of these diseases over time, but the idea of a cure is still tantalizing. So, that's amazing to learn.

As we begin to wrap up our conversation, I wonder if you could talk to the audience about those potentially common misconceptions or misunderstandings about genetics and genetic medicine that may be out there that you'd like an opportunity to maybe set the record straight on today.

Dr. Jennifer Cohen: I think even for conditions where we don't have a single treatment, such as a medication or a gene therapy in the pipeline, a lot of genetic diseases can still be managed. And I think that's an important distinction and something we need to recognize, that early diagnosis, even for these conditions where there isn't necessarily a specific treatment or gene-targeted treatment for them, we need to recognize that early management, such as early intervention with therapies like physical therapy, speech therapy, occupational therapy, can really alter in a positive way the course of a child's life. And so, I always advocate for early diagnosis to help families and children get those services that might be able to help manage the disease and really improve quality of life for everyone involved. And so, that shouldn't be tossed aside as not being helpful or not being enough. That might be where we are for a particular disease, especially when we get into the ultrarare disease space where there's maybe only 50 patients in the world that have a certain condition. There may not be a treatment, there may not be a cure in the pipeline, but management and looking at other conditions that might be similar, learning from those conditions and providing optimal care to the patient is really critical and important to recognize as having a crucial role in the family's life as well.

Host: Jennifer, if you were going to leave our audience with one takeaway, one pearl of wisdom from this conversation, what would it be?

Dr. Jennifer Cohen: I think the idea that knowledge is power and knowing things early. While it may be overwhelming at first, in the end can be really beneficial to a child's health. And so, I'm a big proponent of learning the most you can about your children's health to benefit them and really optimize the care that they get so that they can live the most healthy life possible.

Host: Well, I think that's supremely well said in a fantastic way to wrap up. So, I like to ask all my guests this question. If you weren't a medical geneticist, who would you be and what would you do?

Dr. Jennifer Cohen: So before I came to medicine, I was actually a professional actor. So, I probably would have continued acting I think, had I not found my love of medicine and children's health. But I think had I found medicine but not found medical genetics, I probably would be in maternal-fetal medicine healthcare hopefully. But I think acting is still a passion of mine and I still enjoy going to the theater and supporting the theater arts even if I'm not the one on stage anymore.

Host: Well, that's wonderful. You know, the biggest benefit of this show for me is to learn more and more about the people with whom I work. And that's really amazing. I love that you have that side to you. So, that's great.

Dr. Jennifer Cohen: Thanks.

Host: Jennifer, I'd like to thank you for being a guest on the show. I hope you'll come back and talk to us again about other topics in genetics and the health of children. Perhaps we'll have a panel with you and Dr. Landstrom and other genetic experts here at Duke. I think that would be very interesting and very fun. Thank you.

Dr. Jennifer Cohen: That would be great.

Host: Pediatric Voices is brought to you by Duke Children's Hospital and the Department of Pediatrics at the Duke University Medical Center here in sunny and very warm Durham, North Carolina.

Pediatric Voices was created by Dr. Richard Chung and by me, Dr. Angelo Milazzo. Debbie Taylor provides a huge assist and keeps us organized. Our podcast is produced by the amazing people at DoctorPodcasting. Thanks to our chairman, Dr. Anne Reed, and the team at Duke Children's for their continued and ongoing support of the program.

You can find the podcast and please hit the subscribe button wherever you find your favorite shows, Apple Podcasts, Google Podcasts, Stitcher, TuneIn, iHeartRadio and Spotify. And please connect with us at dukechildrens.org, at Facebook/DukeChildrens; and I guess it's called X now, not Twitter, x/duke_childrens. We'd love to hear from you, so leave us a review. Thanks for being a part of the show. We'll see you next time.