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Conversations with the leaders advancing rare disease care. Rare Discussions is CheckRare's flagship interview podcast featuring conversations with leading physicians, researchers, patient advocates, and industry experts. These episodes explore advances...
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Conversations with the leaders advancing rare disease care.
Rare Discussions is CheckRare's flagship interview podcast featuring conversations with leading physicians, researchers, patient advocates, and industry experts. These episodes explore advances in diagnosis, treatment, research, and patient care across the rare disease landscape.
Whether highlighting groundbreaking therapies or sharing expert clinical perspectives, Rare Discussions highlights the experts who are shaping the future of rare disease medicine.
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Rare Discussions is CheckRare's flagship interview podcast featuring conversations with leading physicians, researchers, patient advocates, and industry experts. These episodes explore advances in diagnosis, treatment, research, and patient care across the rare disease landscape.
Whether highlighting groundbreaking therapies or sharing expert clinical perspectives, Rare Discussions highlights the experts who are shaping the future of rare disease medicine.
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1 LUG 2026 · Spinal muscular atrophy (SMA) has undergone a remarkable transformation over the past decade. Drs. Nancy Kuntz, Alicia Henriquez, and Angela Lek discuss how advances in disease-modifying therapies have fundamentally changed the outlook for children living with SMA, leading clinicians to rethink what constitutes a successful outcome in SMA care.
Over the past decade, the management and treatment of spinal muscular atrophy (SMA) have been transformed, resulting in remarkable effects on young patients’ neuromuscular function status, mobility, and quality of life. These improvements would have been difficult to imagine just a few years ago and challenge clinicians, researchers, patients, and families to rethink what is defined as a successful outcome in SMA care.
According to Nancy Kuntz, MD, a child neuromuscular specialist from Lurie Children’s Hospital, Chicago, when before the use of newborn screening and the latest treatments, the main outcome of interest was prolonged patient survival. Today, achievable patient outcomes include sitting upright, and walking independently. This is a long way from the palliative view of SMA care. The use of standard measurement scales of patient outcomes need to keep up with evolving expectations of caregivers and patients.This will require objective data, like biomarkers, x-ray changes, and the ability to see significant changes in motor scale scores, focused on types of motor function that is important to patients.
Alicia Henriquez, MD, a pediatric neuromuscular specialist from Seattle Children’s Hospital, pointed to one of the standard functional scales used in therapeutic clinical trials, the Hammersmith Functional Motor Scale Expanded (HFMSE). It is based on 33 distinct functional domains, but not all of those domains are of equal importance to patients and caregivers. And a change in HFMSE scale measurement may not be statistically significant for the purposes of clinical trials, but that incremental change in one domain may be highly important for the individual.
The scales do a better job of detecting major changes in function but not what those changes mean for patients.The Muscular Dystrophy Association (MDA) is helping to bring more light to this issue. Angela Lek, PhD, Chief Research Officer at the Association, described how MDA is sponsoring registry studies to collect real-world outcomes of individuals with SMA. This may result in patient-reported measures that may more-directly reflect improvements that patients believe are important.For more information on SMA visit https://checkrare.com/spinal-muscular-atrophy-a-decade-of-progress/ Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
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8 GIU 2026 · Robert Rapaport, MD, Professor of Pediatric Endocrinology, and Director of the Comprehensive Growth Center at the Icahn School of Medicine, Mount Sinai Medical Center, New York City, discusses the causes of growth hormone deficiency and its treatment. Growth failure in children is a considerable challenge for parents and pediatricians, with clinical and social stigma implications that may be avoided with early diagnosis.
The most important issue in young patients with growth failure is to detect it early, according to Dr. Rapaport. “As soon as you see a major deviation from the [expected growth chart] norm, act on it, even at age 2,” he emphasized, “because we know that best outcomes result from early detection.” A growth failure diagnosis is delayed or underdiagnosed in minority groups; it is underdiagnosed in girls relative to boys. In most cases, children are referred to the Comprehensive Growth Center by pediatricians and primary care physicians, and it should be monitored from birth. Growth failure in children can be caused by growth hormone (GH) deficiency, malnutrition, celiac disease, pituitary tumor (which suppresses the release of growth hormone) or a very rare genetic deletion. Once the potentially nonendocrine causes of GH deficiency are excluded, then causes related to the hypothalamus–pituitary-thyroid axis should be investigated, said Dr. Rapaport.
Growth hormone stimulation testing and low blood levels of insulin-like growth factor (IGF) and IGF-binding protein concentrations can help confirm GH deficiency as the cause. However, low IGF-1 levels can also be caused by excessively high GH levels. In children diagnosed with GH deficiency, weekly GH injections are typically prescribed. In addition to monitoring these children for potential side effects of the GH injections, Dr. Rapoport recommended that they should undergo lab testing for IGF-1 blood concentrations every 3 to 6 months, until the bones fuse (signaling the conclusion of growth). Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
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3 GIU 2026 · Christopher Romero, MD, a pediatric endocrinologist at Mount Sinai Medical Center, New York City, and Associate Professor of Pediatrics at the Icahn School of Medicine at Mount Sinai discusses arginine vasopressin deficiency. The name of the rare disease central diabetes insipidus was changed in 2024 to better reflect its etiology.
Central diabetes insipidus, a rare disease, is unrelated to the common medical problem diabetes mellitus, other than they are both problems related to endocrinologic dysfunction. Whereas diabetes mellitus involves pancreatic function and the production of the hormone insulin, central diabetes insipidus involves the pituitary gland and regulation of the hormone vasopressin. Dr. Romero stated that a new name for central diabetes insipidus was introduced in 2024—arginine vasopressin deficiency (AVP-D) to reflect the difference and relieve misconceptions caused by the traditional naming.
The central issue with AVP-D is the function of antidiuretic hormone, which regulates water concentrations in the body. Pediatric and adult patients with this vasopressin deficiency (which mediates antidiuretic hormone levels) excrete more urine than patients without the deficiency. “It causes these patients to drink more, to make up for the water loss,” said Dr. Romero, “resulting in kids being thirstier and having to use the bathroom more often.”
As a result, AVP-D can lead to weight loss and loss of appetite, dehydration, and electrolyte abnormalities. He also pointed out that the abnormal cycle of drinking and urination in children interferes with school work and performance.
“Unless you’re aware of [AVP-D], you may miss the diagnosis,” said Dr. Romero. The pituitary gland is involved with so many functions, and symptoms only slowly evolve. Issues with the onset of puberty and growth may hint at the pituitary source of the problem.
Historically, treatment was managed with an oral formulation of vasopressin, which was first available in the 1970s. An intravenous form was available in inpatient settings. A nasal spray formulation was subsequently developed, and is useful particularly with older children. Dr. Romero pointed out, figuring out the correct dosage for an individual pediatric patient is key; every child with AVP-D is different in terms of how much water they lose during the drinking–urination cycle. “Even though the oral form was effective, only two dosages were available. You have to titrate the dose to balance the water loss,” he emphasized.
The introduction of Desmoda in February 2026, an oral solution of desmopressin acetate 0.05 mg/mL, allows for easier titration. The solution may be easier to take than the pills for young children, and caregivers may have a better idea of precisely how much medication the patient is getting. For those reasons, Dr. Romero believes this formulation may be the best option for young pediatric patients with AVP-D.
Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
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18 MAG 2026 · This accredited continuing education program is supported by an educational grant from Blueprint Medicine.
It provides timely and practical education on systemic mastocytosis (SM). To obtain CME credit, visit https://checkrare.com/learning/p-systemic-mastocytosis-recognition-diagnosis-and-clinical-management/
SM is a rare, chronic disorder driven by aberrant mast cell accumulation across multiple organ systems. Although diagnostic criteria are well established, a recent natural history study found that the average time to diagnosis is nearly five years. This prolonged delay—largely due to limited awareness of SM and its early symptoms—often results in unnecessary disease progression and inappropriate treatment. To address this clinical gap, this activity, led by Daniel J. DeAngelo, MD, PhD, Chief, Division of Leukemia at the Dana-Farber Cancer Institute, Harvard Medical School, in Boston, MA, provides an overview of the early signs and symptoms of SM, outlines the appropriate diagnostic criteria and tools, and reinforces the importance of timely referral and testing for these patients to be properly managed.
Led by a clinical expert with experience diagnosing and treating patients with SM, this 45-minute CME program will highlight early signs of SM, outline diagnostic criteria and tools, and reinforce the importance of timely referral/testing.
Target Audience
This activity has been designed to meet the educational needs of physicians specializing in hematology, dermatology, gastroenterology, immunology, and family practice. Other members of the care team may also participate.
Learning Objectives
After participating in the activity, learners should be better able to:
Describe the early symptoms of systemic mastocytosis and its clinical relevance.
Apply best practices to diagnose systemic mastocytosis more efficiently.
Faculty
Daniel J. DeAngelo, MD, PhD
Chief, Division of Leukemia
Dana-Farber Cancer Institute,
Harvard Medical School
Boston, MA
Disclosure Statement
According to the disclosure policy of the Academy, all faculty, planning committee members, editors, managers and other individuals who are in a position to control content are required to disclose any relationships with any ineligible company(ies). The existence of these relationships is not viewed as implying bias or decreasing the value of the activity. Clinical content has been reviewed for fair balance and scientific objectivity, and all of the relevant financial relationships listed for these individuals have been mitigated.
Disclosure of relevant financial relationships are as follows:
Faculty Educator/Planner
Dr. DeAngelo discloses the following relevant financial relationships with ineligible companies:
Consultant: Amgen, Autolos, Blueprint Medicines, Incyte, Jazz, Novartis, Pfizer, and Takeda
Research Support: AbbVie, Glycomimetics, Novartis, and Blueprint Medicines
Data Safety Monitoring Board: Daiichi-Sankyo
Other Planners for this activity have no relevant financial relationships with any ineligible companies.
This activity will review off-label or investigational information.
The opinions expressed in this educational activity are those of the faculty, and do not represent those of the Academy or CheckRare CE. This activity is intended as a supplement to existing knowledge, published information, and practice guidelines. Learners should appraise the information presented critically, and draw conclusions only after careful consideration of all available scientific information.
Accreditation and Credit Designation
In support of improving patient care, this activity has been planned and implemented by American Academy of CME, Inc. and CheckRare CE. American Academy of CME, Inc. is Jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Physicians
American Academy of CME, Inc., designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Other HCPs
Other members of the care team will receive a certificate of participation.
There are no fees to participate in the activity. Participants must review the activity information including the learning objectives and disclosure statements, as well as the content of the activity. To receive CME credit for your participation, please complete the pre and post-program assessments. Your certificate will be emailed to you within 30 days.
Privacy
For more information about the American Academy of CME privacy policy, please access http://www.academycme.org/privacy.htm For more information about CheckRare’s privacy policy, please access https://checkrare.com/privacy/
Contact
For any questions, please contact: CEServices@academycme.org
Copyright
© 2026. This CME-certified activity is held as copyrighted © by American Academy of CME and CheckRare CE. Through this notice, the Academy and CheckRare CE grant permission of its use for educational purposes only. These materials may not be used, in whole or in part, for any commercial purposes without prior permission in writing from the copyright owner(s). Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
24 APR 2026 · Merlin G. Butler, MD, Medical Geneticist and Professor, Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, and one of the pioneers in Prader–Willi syndrome research, discusses the clinical features of this very rare disease and the critical importance of early identification.
Prader–Willi syndrome was first reported in 1956, and deletions in chromosome 15 were first identified in the 1980s. Dr. Butler has been working on the genetics of Prader–Willi syndrome since that decade.
Dr. Butler said that Prader–Willi syndrome was the first example of a disorder caused by “genetic imprinting,” in which it matters whether genes are contributed by the mother or the father. In 70% of the cases of this disorder, the father’s contribution is missing from chromosome 15q13, and 25% of cases are the result of both copies of chromosome 15 being from the mother (referred to as “disomy”).
Babies born with this genetic anomaly have severe hypotonia, and they have no interest in sucking or feeding. They often have decreased muscle mass and energy. “These infants look like they have a major problem at birth,” stated Dr. Butler. They need to be tube-fed. Once a genetic cause is suspected, Prader-Willi syndrome is quickly diagnosed; it is a very rare disease that also has very unique features. Pediatricians may see only one of these patients every 10 years. Therefore, according to Dr. Butler, “it is the parents who oftentimes make the diagnosis, through what they have seen on the Internet, prompting genetic testing.”
Despite their problems with feeding in the neonatal period, infants with Prader–Willi syndrome will begin to gain an interest in feeding by around age 2 to 3 years. By age 6 years, they develop hyperphasia. “Once their appetite is turned on,” he said, “it is never off.” Uncontrolled, this results in obesity and life-threatening conditions, such as type 2 diabetes and stomach rupture.
Early identification is key, and determining the genetic subtype is extremely important to building a multidisciplinary care team. There are seven different genetic subtypes, which can impact outcomes and management. Typically, the care team will include the medical geneticist and genetic counselors, endocrinologists (to manage the use of growth hormone and diabetes-related treatment), dietitians to manage and monitor caloric intake, mental health experts to address behavioral issues and the risk of self-injury, gastroenterologists, and potentially even sleep medicine professionals. The specialists comprising the care team will change over the patient’s lifespan; occupational therapy and speech therapy may well be required as the patient ages.
The treatment of hyperphagia associated with Prader–Willi syndrome, the number 1 issue, is a particularly active area of research. The idea is to avoid the onset of obesity, which can lead to most of the comorbidities and complications. Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
17 FEB 2026 · Dinesh Patel, PhD, CEO of Protagonist Therapeutics, discusses the New Drug Application (NDA) submission to the US Food and Drug Administration (FDA) for rusfertide to treat adults with polycythemia vera (PV).
PV is characterized by excess red blood cells in the bloodstream, increasing the risk for blood clots. Most cases of PV are acquired and occur more frequently in men than in women. The condition has been associated with genetic changes in the JAK2 and TET2 genes. Rusfertide is an investigational first-in-class subcutaneously administered hepcidin mimetic peptide designed to regulate iron homeostasis and red blood cell production to control hematocrit levels in patients with PV.
The NDA submission is based on positive 32-week primary analysis and 52-week results from the phase 3, global, randomized, placebo-controlled VERIFY clinical trial (NCT05210790). In this study, patients receiving rusfertide plus standard of care therapy demonstrated a substantially higher response rate compared to placebo plus standard of care, including durable hematocrit control, a reduction in phlebotomy requirements and improvement in pre-specified patient reported outcome endpoints.
Rusfertide has received Breakthrough Therapy Designation, Orphan Drug Designation, and Fast Track Designation from the FDA. Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
22 DIC 2025 · Alan Beggs, PhD
Director of the Manton Center for Orphan Disease Research
Sir Edwin and Lady Manton Professor of Pediatrics, Boston Children's Hospital
Harvard Medical School, Boston, MA, USA
Julie A. Parsons, MD
Haberfield Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine, Children's Hospital Colorado
Aurora, CO, USA
The ASPIRO Clinical Trial is on clinical hold since September 2021. In this part, Doctors Beggs and Parsons will discuss key issues on gene therapy development.
Question: Is there a standardized immunomodulation regimen being considered for gene therapy?
Julie A. Parsons, MD
As I mentioned, right now, I think there are a number of different concepts that are being utilized. We don't really have a recommended standard regimen at this point. There are a number of different trials that are ongoing looking at trying to answer this question. In some of the clinical trials, there is an immune modulating regimen that is being put in place but being looked at. There isn't anything that we have as a standard at this moment for all gene transfer therapies, but I'm hopeful that we will come up with something that really makes sense in each patient population as we go forward with specific gene transfer therapies.
Question: What are the long-term implications, safety and efficacy of a one-time gene therapy in pediatric patients with neuromuscular diseases?
Alan Beggs, PhD
One question is the efficacy. For example, Donovan Decker's story, he had an experimental treatment of one muscle. It was a phase one safety trial, and he knew that nothing was going to come of it in terms of direct benefit to him. As a result, though, 25, 30 years later, he still has a tighter against AAV vectors. He's not a candidate for gene therapy under current protocols, although there's a lot of work going on to redosing. But for now, it's a one-time treatment. What you get is what you get, and there's not a chance to go back and do it again.
The other question is durability. We really don't know about the long-term durability for these treatments. I should say that, for example, in the studies that we did, David Mack, who's here in the audience, managed a dog colony for a dog model of excellent tubular myopathy. Those animals lived 10 years in a... We never used the C-word, but they were cured. They were healthy, happy, normal dogs who would have had to be put down at 6 months of age otherwise. And then, as we heard, I'll let you talk about the concern for unanticipated SAEs as time goes on, but I think there's other aspects we need to think about.
Julie A. Parsons, MD
Yeah. I think that this is really the key question that all of us are going to need to help answer over the next several years. Efficacy, we're looking at outcomes, and outcomes come in a variety of flavors. I think we do a decent job with motor outcomes. We don't do a decent job with some other outcomes. I think we need to look more broadly in terms of what we mean in terms of beneficial outcomes and really take some of those cues from the patients themselves about if these are efficacious treatments, because, again, the risk is high as we deliver these agents, and we need to know that it's worth it to the patients and families.
In terms of safety, we're working on it. There are all sorts of things that are coming forward as issues with these patients. I think that collectively as a community, that our responsibility is to follow patients for the long term. There are lots of registries and outcome studies. We're not very good as a community about reporting adverse events to central groups. We're not great about broadcasting that to each other in real-time. I think those are things that we really need to work on as a community in terms of helping with the safety issues so that we all have a communal better understanding of what some of those issues are. Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
22 DIC 2025 · Julie A. Parsons, MD
Haberfield Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine, Children's Hospital Colorado
Aurora, CO, USA
How have programs adapted to the experiences from clinical trials? I'm just looking at SMA because we've had SMA. We've had onasemnogene around for the longest period of time. We want to always confirm a diagnosis and know that the patient is right. We do antibody testing for these disorders prior to delivering the AAV therapies. We have to know that the product that is incredibly expensive is handled appropriately by the institution. Dealing with the pharmacy, making certain that you handle the agent properly, patients need to be pretreated at this point with prednisone, and that really has to happen so that you know that they're ready for treatment, that they don't have any infections prior to treatment.
Then we need to monitor and provide medication and follow-up afterwards. As I said, I think this is really, really important to make sure that you're connected well with the patient. If you live in an area as we do, that has a huge catchment area with patients that come from hundreds of miles away, sometimes they need to stay with us for a period of time, so that we can ensure the safety and follow-up of these patients after we deliver gene therapies.
Again, a recurring theme is the patients that you're treating who are not in a clinical trial are not the homogeneous, well-selected patients. It's really all actors. The population that you're treating commercially is very different. We're now moving into treating patients with larger body masses and older ages. We don't always know, because those patients haven't really been included in the clinical trials. We don't really know what some of the effects are going to be with that group of patients as well.
I am a neurologist. I am not an immunologist. I have had to learn a lot of immunology at this point, but it's still not sufficient. I think that we also need to reach out to our subspecialist colleagues who really do have more experience than we do to try to help us with some of these issues, because as we look at these viral vector capsids and the transgenes, we have to say, is there something that we can do to mitigate the immune response that we're seeing when we're giving massive doses of these agents and really taxing the immune system in our patients?
Looking at possibilities, we give steroids, and that's really what we've done. That was what was done in the early clinical trials with MENDEL. It's like, okay, prednisone, that's all we have to do is we give steroids and everybody will be fine. That really isn't maybe the answer. As we have more information, we know that we're going to start with steroids, but we're really going to look at, is there a way to block both the B-cell response, the T-cell response? Is there something that we can do so that we don't have to sit on the edge of our seats and not sleep for months after we treat these patients?
At least in a trial, was done looking at patients who were treated just with corticosteroids. Those patients had rapid increases in IgM and IgG. There's complement activation. Both the adaptive and the acute immune responses are triggered. That's really what we're doing as standard practice right now, but in the trial looking at treating patients and pretreating patients with rituximab blocking B cells and sirolimus and corticosteroids, then no significant change in IgM, IgG.
Is that something that we should be doing? I think that some of the clinical trials that are being set up are looking at instituting some of these immune-modulating features to see whether or not their outcomes are improved. Can we do anything proactively to prevent our patients from having some of these very severe events or fatalities? I think that's really what we need to be looking at now. I think we are looking at that as a community, and to me, is a story that is still unfolding in terms of how we keep our patients safe.
In the next part, Doctors Beggs and Parsons will discuss key issues on gene therapy development. Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
22 DIC 2025 · Julie A. Parsons, MD
Haberfield Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine, Children's Hospital Colorado
Aurora, CO, USA
Now, with our collective experience, we can at least put together the information that we have in terms of what can we expect and what's the timeline that we expect in terms of our patients having reactions. I will tell you, and I've said this multiple times, when I deliver a gene transfer therapy, I hold my breath for 2 months. Now, maybe it's going to have to be extended to a year, but it's typically at least for 2-3 months. It's like, okay, what's going to happen? You sit on the edge of your seat on pins and needles, going, "Is this kid going to be okay or not?" I think that's the appropriate response to have in terms of the light of things that have happened over time. We have to be really careful.
We have a little bit of a framework now to say, when do we need to be really excited? We know that our patients, most all of them, are going to develop a transaminitis, and that ends up happening early on, but we get a couple of peaks. We get really excited that the 4-8 week time point with transaminitis looking for liver failure.
The cholestatic liver disease that happened in the patients with X-linked MTM happened a little bit later, so Week 2, all the way out to six months afterwards. The acute cardiomyopathy a little bit earlier, so we're looking a little bit earlier for that effect. TMA, usually the end of the first week to about 2 weeks is when we would expect that to come in. Then the transgene-related myositis and immune-mediated myocarditis, weeks, maybe 2 to a couple of months.
How do we adapt our gene transfer programs to the clinical trial experience? I think that there are a couple of points that are important. One is that the outline that I showed you, there are some disease-agnostic issues that come up with transaminitis, with TMA. I think there are some final common pathways related to the immune responses that we see with these patients. Then there are going to be some disease-specific disorders that are going to come up with each of these therapies and agents.
We need to have good communication, honestly, in real-time. I still don't know that we have a good mechanism for that as a community, but to share these adverse events that come up so that we can all learn as a collective about what to expect, what to anticipate, and how to best take care of our patients. We know now how we need to monitor patients closely from a laboratory standpoint, from a clinical exam standpoint, and we really need to work on how are we going to mitigate some of these risk issues that we have with these patients.
I think the collaborative aspect, particularly at meetings like this, is important. Last year, for the people that were at MDA, you remember that we really spent a lot of time looking at gene transfer delivery. Many of us got together as providers and actually met together to say, "Is there something that we can think about in terms of best practice or consensus in terms of how we would want to manage patients or how we'd want to share information?"
Now, actually, on the MDA website, we really do have some guidelines, and there will be a publication coming out shortly that we'll have this available to everybody again. It's not necessarily the right answer, but it's at least from a collective experience, what's the best way that we can go forward? Some of the suggestions were that the adverse events right now, we can put them into some a predictable timeline, but we don't really know all the risks at the time of dosing.
We know that gene transfer therapy can be safe for the right patient at the right time for the right disorder. That's really what we want to do. There's a Neurotherapeutic window between efficacy and toxicity. How are we adjusting that? What are we working on to make sure that we're getting that right? The preclinical data is helpful, but it's never the full story. Any time we go from a homogeneous population that we see in a clinical trial to a heterogeneous population, as we throw this out to the world, we're going to have new issues that arise, and we need to be aware and ready for those.
We want to be able to predict what happens, but we can't always do that. Then follow-up is so important. The post-marketing study, sharing adverse events, sharing experiences, I think, is really important as well. Clinicians really should be familiar with this entire field before ever delivering gene transfer therapy. I don't think that every site should be delivering gene transfer. I think that from an institutional standpoint, you need to be ready. You need to have a team who knows what they're doing and knows how to handle the issues and the problems, or you need to have lifelines set up in advance if you're going to deliver these treatments. Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
Explore additional physician interviews, podcasts, CME activities, and rare disease resources at CheckRare.com.
Subscribe to the CheckRare Podcast Network for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community.
Part of the CheckRare Podcast Network: Trusted conversations, news, education, and expert insights across the rare disease community.
22 DIC 2025 · Julie A. Parsons, MD
Haberfield Endowed Chair in Pediatric Neuromuscular Disorders
Professor of Clinical Pediatrics and Neurology
University of Colorado School of Medicine, Children's Hospital Colorado
Aurora, CO, USA
The gene transfer trials for musculoskeletal disorders, if we look at musculoskeletal and neurologic disorders, we really do have the highest success rate in terms of treatment, but we also carry the highest incidence of treatment-emergent severe adverse events. And why is that true? Yesterday, when we were hearing about Donovan as well, we looked and said, When the first gene transfer therapies were started, he had a single muscle that was injected.
When we look at Luxturna, we injected the retina. Now, what is happening with these disorders is that we're giving these huge, massive doses of viral vector to patients. There haven't been a lot of gene transfer therapies that have reached the market. But you saw yesterday, so many gene transfer therapies being worked on, but there are very few that have actually come to market. There are a couple of reasons for that.
One is with the indications that we have, we know that the musculoskeletal disorders are most likely to achieve benefit, but there are the high risk of severe adverse events. Route of Administration, IV, for most of our disorders is the way we're going. We may end up having some Intrathecal therapies as well that are coming on board, but right now it's IV, and that means, a huge dose of this viral vector and antigenic risk that is being administered.
In the vector design now, we actually have more specific vectors as well as promoters that are being utilized to really target specific tissues, so that we're able to focus in a little bit more on the tissues that we want to have affected. And then the dose has gone from these little tiny local injections to really systemic, much broader. And now our patients, are larger. So we're giving a viral genome per kilo dose that is just massive as we look at that.
Then there really are challenges in terms of the translation of clinical trials to commercial treatment with these agents. And we don't always know, we're not always great when we do tests in clinical trials in small populations, about when that's broadened to the commercial availability and we hit larger heterogeneous populations.
There are safety issues arising from these therapies, and I think that we have some experience now, certainly with the three diseases that I mentioned at the beginning, in terms of collecting some data and information to have a little bit more of an idea what to expect. Although to me, the recurring esteem is always, expect the unexpected. Because we still are learning about this.
Hepatotoxicity. We know that transaminitis is something that we see in almost every gene transfer therapy that has been delivered, and we have to watch really, really closely and follow our patients closely for this. We also have to select patients that we don't think have risk for additional liver injury or underlying liver pathology, because as we found out in the XLMTM boys, we missed that. Thrombotic Microangiopathy. We look at this disorder. We've had deaths in SMA from TMA. We have Duchenne patients that have had TMA.
This is scary because as many of us as clinicians who have treated patients, you know that we end up getting thrombocytopenia. So is that it this time, or are they going to be fine, or the platelet is going to go back to normal? This is another one that we have to watch really, really closely for. Cardiac Toxicity. We have had cardio myositis. We've had deaths from cardiac toxicity.
Something really, really important for us to think about. In little kids, vomiting could be a sign of cardiac myositis. And for most of us who've treated patients with gene transfer therapy, what's one of the first issues that you get?
You get nausea of vomiting, they don't feel good. So is that myocarditis or is it just a standard side effect that we're seeing with treatment? Importantly, as we discovered, there actually can be an immune response to the transgene. It's not just the viral vector capsid, it's actually the transgene as well. That was discovered in patients who were treated for Duchenne. So that's a really important thing in terms of looking now at what's our patient's selection and how do we pick the right patients.
Next part, Dr. Parsons will discuss understanding and preparing risk factors associated with AAV gene therapies. Rare Discussions is produced by CheckRare, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community.
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Conversations with the leaders advancing rare disease care. Rare Discussions is CheckRare's flagship interview podcast featuring conversations with leading physicians, researchers, patient advocates, and industry experts. These episodes explore advances...
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Conversations with the leaders advancing rare disease care.
Rare Discussions is CheckRare's flagship interview podcast featuring conversations with leading physicians, researchers, patient advocates, and industry experts. These episodes explore advances in diagnosis, treatment, research, and patient care across the rare disease landscape.
Whether highlighting groundbreaking therapies or sharing expert clinical perspectives, Rare Discussions highlights the experts who are shaping the future of rare disease medicine.
mostra meno
Rare Discussions is CheckRare's flagship interview podcast featuring conversations with leading physicians, researchers, patient advocates, and industry experts. These episodes explore advances in diagnosis, treatment, research, and patient care across the rare disease landscape.
Whether highlighting groundbreaking therapies or sharing expert clinical perspectives, Rare Discussions highlights the experts who are shaping the future of rare disease medicine.
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