Rare Discussions

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.


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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.


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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.


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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

As we talk about the gene transfer therapies and the modalities that we have to use, it's really interesting. Yesterday, with our keynote speaker, you could see this logarithmic growth of the use of gene transfer therapies for these disorders. If you look at the Venn diagram, you can see that really 27% almost of gene transfer therapies that are used are in musculoskeletal and neurology. For many of us as neurologists, we also take care of metabolic disorders.

We really own right now this landscape, and of course, our two approved modalities are Onasemnogene and Delandistrogene. We're going to look at three different disorders, monogenic disorders, monogenic diseases, to typify what we look at in terms of some of the risks and benefits of these treatments. SMA, Duchenne, and X-linked myotubular myopathy are all rare disorders. They're all diseases that have a high unmet medical need and a significant disease burden.

I think they're all good in terms of typifying where we are clinically with these disorders. The first question is, is it worth it? Are these effective treatments? We know from looking at the information about SMA that just looking early on, we know that if we treat kids early, that we do see a marked improvement in motor scores for kids that are treated early with Onasemnogene.

In Duchenne, we have information that there is at least some improvement in the 4-5-year-olds in terms of motor skills treated with Delandistrogene. In terms of X-linked MTM, which was a very dramatic improvement, you could see that for boys who were basically traked, vented, and had no mobility, the bottom line, the blue line, is actually looking at ventilator dependence. Are they effective? Yeah, they're effective, but then we have to say, okay, what's the downside?

The downside is that there's tremendous risk associated with treatment with these agents. If we really look at the sobering facts, we know that with SMA, there have been deaths, there have been fatalities related to thrombotic microangiopathy to patients who have liver failure, a couple of patients have died. With Onasemnogene, this is 4,000 plus doses that have so far been given. With Duchenne, unfortunately, many of us got the letter yesterday talking about an additional death in a patient treated with commercial Delandistrogene.

We also know with some of the other agents, like fordadistrogene, patient died of heart failure, cardiac arrest, another patient who had acute respiratory syndrome with pulmonary edema. Again, we look at this and say this is significant. With X-linked MTM, as Alan said, there were some unanticipated deaths, four deaths from patients who ended up having cholestatic liver diseases that really wasn't anticipated prior to the patients being treated with the animal models and all that we had. Then many of you have heard about the patient with Rett syndrome who had a systemic hyperinflammatory syndrome. Again, these are rare disorders. They have a high disease burden, but the risk of treatment is significant.

In the next part, Dr. Parsons discuss factors impacting safety and efficacy of AAV-mediated gene therapies.


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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

The challenges that you've heard about are real. Some of them I think we could have foreseen others. There was no way to know until we actually started treating patients in clinic. But we now know that there are immune responses and also responses just to the viral load. As Julie mentioned, we're giving massive doses to these patients on the order of one times ten to the 14 viral genomes per kilogram.

Think about the fact that when these capsids are manufactured, there's a certain percentage of empty capsid. The amount of protein that's being delivered to these patients can be massive. One of the approaches to mitigate some of the risk would be to lower the dose. While early studies demonstrated that in order to get adequate delivery to skeletal muscle, you need to give these very large doses. But what if we could engineer a viral capsid that would be potent at lower doses?

There has been quite a bit of research in this area that's ongoing, and some new next generation vectors that are just starting to enter the clinic. In particular, there are a class of Myotropic viral vectors or capsids so-called RGD vectors. RGD refers to arginine, glycine, and aspartic acid, which are three residues which, when present at a particular point in the viral capsid proteins interact with integrin receptors that are specific for skeletal muscle. These viral capsids home to skeletal muscle and can deliver their genetic payload at much lower doses. There was one group of these developed in Germany by Theo Grimm's lab.

These were the so-called AAV Myos, and simultaneously in Boston at the Broad Institute, a group of capsids was developed that were called Myo AAV. These were both based off of an AAV nine backbone. It's basically an AAV nine legacy vector with these three amino acids changed. Now Solid Biosciences also has their own independently derived vector that I believe is also an RGD vector. These vectors give us the potential then for more efficient and specific delivery to muscle cells.

They may or may not target the liver depending on the particular virus. Some of them the risk to the liver is mitigated by delivering a lower dose. You can also develop these vectors in a way that will be liver targeted, that specifically less of it gets delivered to the vectors. These would be really, in my mind potentially third generation vectors.

Strategies, there are a number of strategies. You heard about the immunomodulation regimens. I just talked about optimizing vector design. Also, Doctor Parsons mentioned earlier the fact that where you deliver so zolgensma is delivered Intrathecally. We get it to the place we need it, and we're less likely to have off target effects through other tissues.

Then improved manufacturing is very important. I mentioned the fact that every viral preparation contains empty capsids. There are ways to minimize the production of empty capsids, and also effective ways to filter out and remove those empty capsids. This is actually a very important aspect that is being developed further by the CMO community. Then in summary, I think it's important to take a holistic approach when we're thinking about the development of AAV based gene therapies for neuromuscular disease.

It starts from the fact that for any given disease we're interested in, we need to define the genetic etiology. Since these are gene directed therapies. We need to pay careful attention to the preclinical animal models. How accurately do they really reflect the human condition? Or are there potentially responses in our human patients that we haven't experienced in the animals? It's important to understand the natural history and the patient population.

Recognize that there's extensive heterogeneity, not just in age and severity, but also potentially in underlying susceptibilities in our patients. We have a group of toxicities that we know about and can anticipate. But as Julie was saying, you need to be really careful and think about any potential unexpected SAEs. And then finally I mentioned the manufacturing aspect, the development of newer vectors and quality control aspects that go into making a safe and effective therapeutic.

In the next part. Doctor Parsons will discuss clinical safety and efficacy observed in AAV mediated gene therapy programs in DMD, SMA, and XLMTM.

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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

Doctors Beggs and Parsons discuss the current status of gene therapies in rare neuromuscular disorders in this eight part podcast series. This is derived from the symposium that was presented at the MDA 2025 conference in Dallas, Texas, in March 2025 and is intended for healthcare professionals only. This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established. In contents of this podcast, shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The ASPIRO clinical trial is on clinical hold since September 2021.

In this part, Doctor Beggs will provide an explanation of AAV-mediated gene therapies.

Alan Beggs, PhD
AAV vectors, which I'm going to be talking about more today, or Adeno associated viral vectors are small viruses. Their DNA gets delivered into the cell and remains extrachromosomal. There are very rare occasional integrations, but the risk of oncogenesis as a result is significantly lower as a consequence of remaining extrachromosomal, though, we do have to think about what happens as the cells divide and potentially the durability of treatment is more limited.

There have been a lot of movement and development over the years, starting back in the 1980s when the first AAV genomes were isolated and sequenced. This led to a development of methods to produce recombinant AAVs that would lack the genes necessary for viral replication, but contain a therapeutic gene you wish to deliver. Through this, the structure of AAVs have been developed. There have been isolation of a number of naturally occurring variants. You've heard of AAV8, AAV9, also RH 74, derived from a rhesus monkey for the RH. These have all been used in clinical trials. Then at the end I'll talk a little bit about directed evolution methods to actually engineer capsids with particular properties that are beneficial.

Throughout this we've identified some of the issues that arise in this. It was initially thought that AAV vectors were non-immunogenic, but in fact there are immune responses not just to the viral payload to the therapeutic protein, but also to the viral vectors, and you're going to hear about that from Doctor Parsons. Over time, as we've come to understand these challenges, we've also been developing approaches to mitigate them. In terms of clinical trials and treatments, the very first studies were done back in the 1970s.

By the early 2000, the very first clinical therapeutic was approved in China. It was actually an oncolytic virus carrying a p53 gene to treat head and neck cancers. By now there are over 40 approved treatments for various types of AAV delivered gene therapies. Of course, the ones we know a lot about are Zolgensma, which was approved in 2019, and Elevidys, which was approved last year. A number of challenges and then also a number of approaches to overcome those challenges. First of all, the preclinical data are not always sufficient to predict the response of a human patient.

For example, in X-linked myotubular myopathy we had mouse and dog models that exhibited a myopathy but nothing else, and yet when we treated human patients, we discovered that patients with X-linked myotubular myopathy actually had a previously only poorly recognized hepatopathology that led to potential liver consequences following gene therapy. The animal models don't always predict the clinical outcome in humans.

Also, we have small disease populations. These are rare diseases. It's important to understand the natural history of these diseases, understand the heterogeneity among the clinical population. It's very important to engage with families and with patients and communities, understand who might be at increased risk to treatment with one of these. This feeds into safety considerations. We need to think also about some of the immune responses. I think we're starting to learn, for example, with the gene therapies for Duchenne, and we know this from SMA that some patients get into trouble and others don't. We need to understand why that may be, and we don't know about the long term effects. This has been very recent.

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Drs. Beggs and Parsons discuss the current status of gene therapies in rare neuromuscular disorders in this eight-part podcast series. This is derived from the symposium that was presented at the MDA 2025 conference in Dallas, Texas, in March 2025, and is intended for healthcare professionals only.
This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established in contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The ASPIRO clinical trial is on clinical hold since September 2021. In this part, Dr. Beggs will provide an introduction to gene-directed therapies.

Alan Beggs, PhD
I'm going to talk now about challenges, a little bit of background in the history and the development of AAV-mediated gene therapies, in particular for neuromuscular disorders. There are a lot of aspects about neuromuscular disease that make it a good group of conditions to target by gene replacement therapies. These are traditionally single gene disorders with known identified oftentimes protein deficiencies, so null mutations leading to lack of a protein.

The primary tissue, the therapeutic target is a skeletal muscle, and so we can target that with the appropriate viral vectors. There's a major unmet medical need and substantial clinical burden for these conditions. As rare diseases, they place a very substantial burden on both health systems and patients, both economically and in terms of personal difficulties.

I like to think about gene therapy, which is generically used for one category of this, to really think about gene-directed therapy. So this would be any therapy directed at the nucleic acids that are either encoding our DNA or are encoding the messenger RNA transcripts. So one approach to a gene-directed therapy can be directed at the RNA level. I think you're all familiar with the Exon-skipping approaches that target mRNA splicing.

There are other methods for either knocking down toxic gain of function messenger RNAs, and there are methods now being developed to edit messenger RNAs. So this represents one class of gene therapy. You can also approach gene therapy at level of DNA by editing or changing the DNA in situ. So various CRISPR-Cas9-based approaches. There's now prime editing and other approaches for genetic engineering that target specific locations, often using bacteria endonucleasis that target with oligenucleotides that target specific sites.

And then finally, there's gene replacement therapy, which is what we're going to spend most of our time on today, which really aims to not take away what's there and replace it, but to replace the missing protein product by providing a copy of the healthy or the complete wild type gene. Often, it can either be integrated into the chromosomes or remain extrachromosomal.

So whether or not that happens really depends on the type of vector or approach you use. You can see here a number of different approaches for transferring in a therapeutic gene. The two most commonly used in clinical trials are lentivirus and AAV, and they have different strengths and weaknesses. Lentiviruses are used frequently for hematologic diseases.

Lentivirus is a member of the retrovirus family and has the characteristic that it actually integrates into the DNA. So lentiviral treatments tend to be long-acting. However, they also suffer from the risk that by integrating into the DNA, you might have site-directed mutagenesis. And there have been known instances of cancers that arose through integration at the wrong site.

In the next part, Dr. Beggs will cover the history and challenges in the development of AAV-mediated gene therapies.


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Nicola Longo MD, PhD, and Mark Roberts, MD

Drs. Longo and Roberts discussed the current status of gene therapies in rare neuromuscular disorders in this eight-part podcast series. This is derived from the symposium that was presented at World Symposium 2025 in San Diego, California on February 4th through 7th, 2025, and is intended for healthcare professionals only.

This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The views, thoughts, and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas.

In this part, Doctors Roberts and Longo will discuss treatment with gene therapies.

Question: Can one administer AAV-mediated gene therapy repeatedly?
Mark Roberts, MD
I think the traditional view would have been no. One can think of gene therapy as a silver bullet. Hopefully, it will reach its target. But if it's not effective, that bullet has been shot, the immunological response has occurred, and it means redosing, at least with that particular vector, may become difficult. But this situation is changing and evolving as we have better understanding of immunological modulation for repeat testing. We were discussing this yesterday evening, weren't we, Professor Longo?

Nicola Longo MD, PhD
Correct. Basically, the current AAV-based gene therapy cannot be readministered. It is either effective, or it doesn't work. The other thing is that even though in theory, one could utilize a different AAV vector with different immunogenicity, there is many times cross-reactivity among the different adenovirus, adeno-associated viruses. Now, there are approaches in animal models in which you give a strong immune suppression to prevent the creation of the immune response against the adeno-associated virus, and at least in the animal model, it has been possible to give some of the gene therapy repeatedly.

The second approach that is being tested is with gene correction therapy, in which by using an RNA guide and the CRISPR/Cas9 system delivered by lipid nanoparticles, you basically correct some of the effective genetic information. Obviously, since this is done by lipid nanoparticles and not by an AAV, the immunity that you create is really not there. You can give this one repeatedly, and in theory, it can be given more than one time. But again, you are absolutely correct. The current gene therapy cannot be given twice, and either it works or it doesn't work.

Question:vWill gene-therapy-treated patients be able to go back to the standard of care or enzyme replacement therapy?
Mark Roberts, MD
I think when we're talking to patients about the potential benefits of gene therapy and the amelioration of the requirement to have these infusions on a regular basis of ERT, the hope is that will work, but they need to be reassured that we can potentially go back to the ERT. Gene therapy is an important treatment, but we don't know the destination of the patient at the beginning, and we have to make it available to them to go back to ERT.

One of the crucial questions, of course, though, is the basis of the immunological reaction that perhaps prevented the gene therapy being effective. If it's against the viral vector, well, okay. If it's against the transgene, not great. If it's against the functional protein, that becomes more difficult. It is somewhat, I think at this time, to be fair to say to patients, think of gene therapy as a trial treatment. It is somewhat a leap of faith and an important observation, of course, for the patient community, but just be aware there may be downsides.

Nicola Longo MD, PhD
They totally agree with Dr. Roberts. In general, they should be able to go back to enzyme replacement therapy if the gene therapy is not effective. However, what we are starting to appreciate is that we need to understand the immune response, not just to the enzyme replacement therapy, but also to gene therapy. What this field is doing is forcing geneticists to deal with the immune response. I feel that historically has not been dealt together. The two things need to be integrated. The advantage of the gene therapy is that the protein is produced endogenously. There should be the development of some degree of tolerance with time in the body towards the endogenous continuous production of a protein.

Now, will that happen all the time? I still do not know. Again, we need to understand much better what is the integration of the immune system with the response to gene therapy in the ongoing clinical trials.

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Nicola Longo MD, PhD
Professor and Vice Chair of Human Genetics,
Allen and Charlotte Ginsburg Chair in Precision Genomic Medicine,
Division of Clinical Genetics, Department of Human Genetics,
University of California at Los Angeles (UCLA), Los Angeles, CA, USA

Mark Roberts, MD
Professor and Consultant Neurologist,
University of Manchester, Manchester, UK
Research Lead for Adult Metabolic Medicine at 
Salford Care Organisation, Manchester, UK

Drs. Longo and Roberts discussed the current status of gene therapies in rare neuromuscular disorders in this eight-part podcast series. This is derived from the symposium that was presented at World Symposium 2025 in San Diego, California on February 4th through 7th, 2025, and is intended for healthcare professionals only. This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The views, thoughts, and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas. In this part, Dr. Longo will discuss ongoing gene therapies in lysosomal disorders.

Nicola Longo MD, PhD
I'm going to present to discuss some example of ongoing gene therapy for lysosomal disorder. There are gene therapy in development for both Fabry disease and some of this involve ex vivo gene therapy, many others involve systemic administration with an AAV, Gaucher disease type 1 that affect the periphery, and Gaucher disease type 2, where the replacement should occur within the central nervous system because this condition affects the brain. There is already one approved gene therapy for lysosomal disorder, which is for the early onset metachromatic leukodystrophy. This has been approved both in Europe and now even in the United States, which consists of ex vivo gene therapy with the administration of an extra gene that restore the function of the defective enzyme. Now there are many others that are ongoing for the same indication. There are gene therapy programs for GM1 and GM2 gangliosidosis, and at least one for Krabbe disease. It is important to know that some of these condition are actually included in the recommended uniform screening panel. Basically, we would have access to patients in a timely manner for some of these conditions. Then there are several gene therapy under development for the mucopolysaccharidoses, including MPS-IH, MPS-II, MPS-IIIA and MPS-IV.

There are different type of lysosomal disorders, the one caused by mutation, integral membrane protein, not enzyme within the lysosome, but protein that are present on the membrane of the lysosome. This gene therapy that have been tested, it is for cystinosis, that it is caused by a defective lysosomal and for Danon disease, which is caused by a deficiency of an integral membrane part. Finally, one lysosomal disorder, which obviously seems a metabolic condition, but it is really not, is glycogen storage disease type 2 or Pompe disease, in which there is the intralysosomal accumulation of glycogen. There are several ongoing clinical trials to try to correct the problem in this condition.
Now, I'm going to discuss some of the most advanced program in the lysosomal storage disorder. This include one for Fabry, which is on an accelerated approval pathway with phase 1 and 2 data, one for Gaucher disease type 1. Obviously, I'm going to discuss the one that has been already approved for metachromatic leukodystrophy. There is one for Hunter syndrome, and the difference of the one for Hunter syndrome, it is an example of the direct administration of gene therapy within the central nervous system.

Finally, there is one ongoing for glycogen storage disease type 2 or Pompe disease in adult patients. In gene therapy for metachromatic leukodystrophy, it was the first gene therapy approved for lysosomal disorder in human, and this requires harvesting the CD34 cell from affected patient and then introducing the [inaudible 00:04:32] gene back in this cell, and then placing them back inside the patient again. This has been very effective in patients who were treated early, and obviously, the treatment needs to occur before there is irreversible brain damage in this patient.

In the next part, Dr. Roberts and Longo will discuss treatment with gene therapies.


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.

Nicola Longo MD, PhD
Professor and Vice Chair of Human Genetics,
Allen and Charlotte Ginsburg Chair in Precision Genomic Medicine,
Division of Clinical Genetics, Department of Human Genetics,
University of California at Los Angeles (UCLA), Los Angeles, CA, USA

Mark Roberts, MD
Professor and Consultant Neurologist,
University of Manchester, Manchester, UK
Research Lead for Adult Metabolic Medicine at 
Salford Care Organisation, Manchester, UK

Drs. Longo and Roberts discussed the current status of gene therapies in rare neuromuscular disorders in this eight part podcast series. This is derived from the symposium that was presented at World Symposium 2025, in San Diego, California, on February 4th through 7th, 2025, and is intended for healthcare professionals only. This podcast includes information about investigational compounds that do not yet have a regulatory approval or authorization for a specific indication. The safety and efficacy of the agents under investigation have not been established, and contents of this podcast shall not be used in any manner to directly or indirectly promote or sell the product for unapproved uses. The views, thoughts and opinions expressed in this presentation belong solely to the author and are subject to change without notice. The contents of this presentation do not constitute an endorsement of any product or indication by Astellas. 

In this part, Dr. Longo will discuss gene replacement therapy in lysosomal disorders.

Nicola Longo MD, PhD
Let's go back a second to gene therapy. Gene therapy obviously has the potential of answering many of the questions that we still have open in lysosomal disorder because they could restore the activity of the lysosome pretty much in the whole body, or at least in multiple tissues. As you have seen, gene therapy can be done ex vivo where we take cells from the affected patient, we correct the gene, or we put an extra gene that it is functional. Then we put them back by doing a bone marrow transplant, basically creating space for the cells that have been genetically modified to correct the lysosomal defect. The biggest approach this is done usually by lentiviruses that they integrate inside the genome.

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.