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.


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, 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.

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 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.

Nicola Longo MD, PhD, and Mark Roberts, MD

Drs. Longo and Roberts 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 WORLDSymposium 2025 in San Diego, California on February 4th-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 the current treatment landscape and limitations in lysosomal disorders.

Nicola Longo MD, PhD
What I want to do today, is just place gene replacement therapy within the current landscape of lysosomal storage disorder treatment therapy. Gene therapy obviously has the potential of treating lysosomal disorder to correct the root cause of lysosomal storage disorder. The gene is defective, and what happen is that you can potentially either fix the gene or bypass the lack of the genetic product. But there are already therapies that are existing and are functioning. Obviously, in many cases, the lysosomal disorder is caused by defective production of an enzyme, which is defective.

We can either replace the enzyme with enzyme replacement therapy, or provide chaperone for specific mutations that retain the synthesis of the enzyme, that however is not very functional. Another avenue that it is being reported is the utilization of substrate reduction therapy. A substrate accumulates, you prevent the synthesis of the substrate to reduce the accumulation of toxic material. What we know now is that this is not enough to produce many lysosomal disorders. In many cases, the lysosomal disorder result sometime in impairment of intracellular trafficking, and sometime in the function of other organelles.

At the end, it results in the activation of the macrophagic system and inflammation. Already we have some therapy acting at this level. The end result of lysosomal storage disorder, there will be cell suffering and cell death, leading to a progression of the disease, and morbidity and mortality. Now, what therapy do we have available already? Obviously, hematopoietic stem cell transplantation has been around for quite some time.

It has been the same thing that we do with gene therapy, except that instead of reintroducing the gene of the subject, we place gene of a subject who is not affected of the disease. This therapy has been proven effective in cases of MPS-1 and alpha-mannosidosis. But in many cases this has to be given way before symptoms start to be affected.

Enzyme replacement therapy has been around for quite some time, starting with Gaucher disease, and now that it is available for a list of diseases that are there, so it's like Fabry, Gaucher, Pompe, different types of mucopolysaccharidosis, alpha-mannosidosis, acid lipase deficiency, 1 neuronal ceroid lipofuscinosis, and Niemann-Pick type A and B.

Obviously the advantage of this therapy, they give back the enzyme that it is defective. But the disadvantage that many time they cannot enter specialized areas such as the brain. There is already the second generation of enzyme replacement therapy that it is available. With this second generation, some of the newer drugs are more effective in terms of cellular uptake, or in terms of having a prolonged half-life and prolonged activity.

Then there are pharmacological chaperone therapy, and the one which is FDA approved is migalastat for Fabry disease, under study is ambroxol for Gaucher disease. The disadvantage of this therapy that only a selected number of mutations respond to this therapy.

Substrate reduction therapy has been introduced for Gaucher disease many years ago with miglustat, and it was followed by eliglustat. Both of them are effective, and some of them more effective than other, simply because of the fewer side effects of eliglustat as compared to miglustat. But at the same time, eliglustat does not pass the blood brain barrier.
\
Finally, the newer agents that are already administered, N-acetyl-L-leucine and arimoclomol, both approved for Niemann-Pick type C, they act more on the downstream effect of the lysosomal storage disorder, either by stabilizing neuronal cell activity or by reducing the inflammation that is present in the brain.

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


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, and Mark Roberts, MD

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. Roberts will discuss lessons learned from gene therapy trials.

Mark Roberts, MD
When we think about the challenges of actually doing clinical trials with these gene therapies, there's a huge development stage in terms of picking the right viral vector with the right surface receptor. That's a major piece of work. That can often take years. The preclinical work is obviously very important as indeed is understanding the natural history because it's really not practical to do placebo-controlled trials of gene therapies.

In contrast to other studies, when we turn to phase 1 and phase 2, you'll notice that the patient numbers are often quite small. One is having to think carefully about surrogate measurements of response. Especially when in phase 3 studies, we may be thinking about withdrawing the existing, for example, enzyme replacement therapy because we believe the gene therapy will then be effective.
That's just a few snapshots of where we've come and there's a lot more work to be done.

In the next part, Dr. Longo will discuss the current treatment landscape and limitations in lysosomal disorders.





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, and Mark Roberts, MD

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
Profesor and Consultant Neurologist,
University of Manchester, Manchester, UK
Research Lead for Adult Metabolic Medicine at 
Salford Care Organisation, Manchester, UK

Drs. Longo and Roberts discuss the current status of gene therapies in rare neuromuscular disorders in this 8-part podcast series. This is derived from the symposium that was presented at World Symposium 2025 in San Diego, California on February 4th-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. Roberts will discuss immune responses and other safety concerns related to gene therapies.

Mark Roberts, MD
Undoubtedly, the immune system is a major issue in these patients. It would be fantastic if we could immunotolerize our patients and indeed prevent the rejection of the therapy. We've talked about the fact that these are viral vectors and of course there may be high seroprevalence of antibodies to these viral vectors, and it's very important in the pre-screening of patients who might be eligible to understand that at the beginning. These of course can have developed over the years and of course can be part of immunological memory and therefore extremely difficult and probably impractical to actually shift.

On giving the treatment though as I think we're all aware there is this problem of the innate immunity and potential therefore for acute toxicities and then a learned or adaptive response with cytotoxic T cells and antibodies which may of course become high tighter neutralizing antibodies and potentially antibodies not only against the viral vector, even the functional protein, even the transgene are all theoretical possibilities with time. The capsid, the transgene, and even the protein product can all potentially induce an immunological event. Of course, all of these would lead to both potential patient changes and then a lack of efficacy of the treatment.

Indeed, there have been some serious and indeed fatal problems in the gene therapy development program as I think we're all aware. Though many of these are thankfully been overcome. Spinal muscular atrophy has a gene therapy which is licensed, but there were early patients who actually had significant problems. A patient of just 6 months of age who developed kidney failure, two other patients who actually developed liver failure.

In Duchenne muscular dystrophy, a very common condition, again there were significant issues and crucially in these patients who all have cardiomyopathy, it was heart failure and cardiac arrest that were big concerns and pulmonary edema and this was seen even with a CRISPR-based technology and is perhaps is best known but has been addressed the excellent myotubular myopathy patients, four patients died and crucially quite a long time after the gene therapy emphasizing the need to monitor these patients extremely carefully and these patients died of cholestatic liver failure albeit that they had a degree of liver dysfunction.

That's changed our screening of course of patients, we're now all looking in myotubular patients for liver involvement and Rett syndrome as well. Now these immunoprophylaxis treatment regimes to hopefully try and reduce the immunological reaction against the gene are certainly evolving.
This is just a summary of some of the other immunosuppressive regimes used in other disorders, for example, spinal muscular atrophy, but Pompe and MPS as examples of LSDs. Certainly these regimes will continue to evolve and are going to be very important in seeking to make sure that these treatments are effective. It reminds me somewhat of what's happened with enzyme replacement therapy that the use of these immunological strategies in infants has revolutionized the utility of those treatments in early patients.

In the next part, Dr. Roberts will discuss lessons learned from gene therapy trials.


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, and Mark Roberts, MD 

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
Profesor and Consultant Neurologist,
University of Manchester, Manchester, UK
Research Lead for Adult Metabolic Medicine at 
Salford Care Organisation, Manchester, UK

Drs. Longo and Roberts 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 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. Roberts will discuss vectors, different strategies, modes of administration and targets in gene replacement therapies.

Mark Roberts, MD
Now in the broader sense, gene replacement therapy seeks to actually deliver genetic material directly into the host cell to influence gene expression. In the most simple idea, one of course has a vector, this is most commonly but not exclusively a virus, which can then be given intravenously for example, and can hope to potentially correct the condition within the individual cells using novel transgenes. Suitable candidate conditions for this as examples of genetic conditions are now well understood. And crucially, this applies not only towards some more recessive, but dominant and even accident conditions.

Across the piece, one can see for example, mitochondrial problems, spinal muscular atrophy as is well known, X-linked myotubular myopathy, Duchenne muscular dystrophy, a very common condition affecting one in 3000 male individuals, Pompe disease of course, an important focus of the meeting here, but other very common conditions, for example, cystic fibrosis, immunological conditions and perhaps obviously very crucial in early work on gene therapy, hemophilia.

Let's now think about the approaches to gene therapy. One can seek to work at the DNA level and gene replacement. In essence, one is trying to put a new transgene through into the nucleus that will ultimately be transcribed and translated and produce the important functional protein that is lost. Gene editing which is a very exciting new technology or CRISPR technology actually seeks to actually modify in vivo the actual mutations that are responsible for the pathogenic production of abnormal proteins and correcting these and actually producing a more normalized protein.

But of course there are also RNA approaches where one seeks to actually repair the mRNA transcripts copied from the mutated gene. For example, this may be a novel approach that could be extremely useful in myotonic dystrophy, a multisystem condition. When we talk about the viral vectors, predominantly we're talking about viruses. Those such as adenoviruses and AAV viruses which have the virtue of not integrating into the host genome or at least not in a large amount, and those which deliberately seek to integrate into host genome such as retroviral or lentiviral systems that may be particularly useful for ex vivo systems.

There are of course other ways to get genetic payloads into the nucleus, various polymers, nanoparticles and even cell penetrating peptides. Nanoparticles in particular is certainly on the ascendant. That being said, in a recent review of the clinical trials in gene therapy, it was certainly the viral vectors that stood out both in direct gene replacement with lentivirus and AAV, but also actually as delivery systems, for example, for gene editing. An example of what one is seeking to do with AAV, so of course one seeking to remove the native DNA, insert the new transgene directly into the vector and of course keen to make sure that there's a high transmission into the capsid producing a recombinant AAV, which then can be given as a treatment and hopefully produce a therapeutic increase in the functional protein that is deficit in the disorder.

In the next part, Dr. Roberts will discuss immune responses and other safety concerns related to 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. Roberts will discuss lysosomal disorders and the potential for gene therapies.

Mark Roberts, MD
I'm going to give an overview of what is gene therapy, emphasizing the current challenges and the development issues and needs that there will be as we try and enable gene therapy for our patients, particularly those with lysosomal storage disorders.

I'm going to try and make a case for why lysosomal storage disorders are an extremely good group of conditions for the potential benefits of gene modifying therapies. Firstly, whilst we all recognize that these conditions are inherently individually rare, they're certainly severe. Collectively, with over 70 LSD disorders, 1 in 5,000 may be afflicted by these conditions ultimately in their life and can be detected, for example, by newborn screening programs.

Secondly, there's certainly a significant clinical burden with these patients with the current standard of care, so a large unmet need exists. Existing enzyme replacement therapies have undoubtedly changed the natural history of many of these conditions, but there are limitations and often initial benefits and later deteriorations.


Unfortunately, for most lysosomal storage disorders, it's only symptomatic treatments and indeed, care that is available for these patients with no specific treatment. Thirdly, these conditions are extremely well-characterized, monogenic singleton and problems of inborn errors of metabolism. We know the functional protein that is deficient in these conditions. Because of that, and knowing that these are critical for lysosomal function, and using preclinical models, we can model the potential benefits of gene therapies very well in a number of systems, including, of course, soon, muscle chip experiments as well.

Finally, with these conditions, they may potentially be really useful targets whilst not perhaps curing the condition, at least ameliorating the phenotype, and enabling the addition of other treatments as well, potentially. I've noted, some of these therapies can be directly delivered to certain tissues, so muscle tissue, which is my main interest, but also, crucially, the central nervous system, which is very important when we consider ameliorated phenotypes, for example, treated by enzyme replacement therapy, but where the children who become the adults have significant learning disability as a major component to their problems.

In the next part, Dr. Roberts will discuss vectors, different strategies, modes of administration, and targets in gene replacement therapies.


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Chair
Professor Yoshikatsu Eto
Advanced Clinical Research Center, Southern Tohoku Research Center for Neuroscience, Tokyo, Japan

Speakers
Dr Nicole Muschol 
International Center for Lysosomal Disorders (ICLD), University Medical Center, Hamburg-Eppendorf, Germany

Professor Patrício Aguiar
Inborn Errors of Metabolism Reference Center, Unidade Local de Saúde de Santa Maria / Faculty of Medicine, Lisbon University, Portugal

Dr Robert Hopkin
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

Professor Yoshikatsu Eto
Welcome to the Chiesi symposium. The title of this symposium, Catching the Clues, Changing the Cause of Lysosomal Storage Disease: Illuminating Complex Pathway of Rare Disease with Fabry Disease, Alpha-Mannosidosis, in Focus.

This is a disclaimer: Following discussion does not focus on or depict any specific products manufactured by any pharmaceutical company. Patient cases are for medical discussion only and reflect the faculty own experience. They represent a typical clinical scenario. This presentation in part and whole may not be reproduced and not copy and not recording.

I'm Dr. Eto from Tokyo, Japan, and the three distinguished speakers: Dr. Nicole Muschol from Germany, Eppendorf University. Professor Aguiar, the Portuguese, The Inborn Errors of Metabolism Reference Center, and also Professor Robert Hopkin, Cincinnati Children's Hospital, United States.
The purpose of this symposium: Explore the patient journey across the LSD continuum, focusing on the unmet needs and diagnosis, and treatment initiation, and long-term management, and utilize case-based discussion focused on Alpha-mannosidosis, Fabry disease to highlight disease-specific challenges. Access where challenge persist in patient journey, and where tailored intervention can improve outcomes.

Introduction of LSD patient journey with a spotlight on Fabry disease, Alpha-mannosidosis. Challenge to the diagnosis and then treatment and monitoring. Common LSD challenges over the patient journey, as shown here, and at least more than 70 different lysosomal diseases known. Incidence is about 1:5,000-1:8,000 in newborn. In the literature, much higher incidence.

Multi-organ manifestation in many organ involved, and clinical heterogeneity are very complicated. The new screen method has been established already. Identify patient presymptomatically. That important by the newborn screening, something like that, early treatment essential. After the diagnosis treatment start, early and the presymptomatic treatment initiation, and usually delayed diagnosis, delayed treatment. Perceived burden of treatment may delay treatment start in patient milder form. Milder form is very difficult in the many cases, and particularly for Fabry disease also.

After the treatment start and then monitoring, as you know, we discussed about the monitoring rely on the combination of clinical assessment, laboratory test, biomarkers, and imaging, and several other factors. Biomarkers and ADA drug assay lack standardization. Actually, the Alpha, and Beta, or [inaudible 00:03:19] Fabry disease, different ADA-titled measurement. Also, the patient experience between clinical visit, ERT infusion is under-reported.

We discuss today two topics, two disease. Alpha-mannosidosis is very rare. In Japan, only few cases, and caused by the deficiency of Alpha-mannosidase, an accumulation of mannose-rich oligosaccharides and inheritance of autosomal-recessive. Age of onset is a very early period and younger period, adult period. Incidence approximately is very rare, 1:500,000.

There are diseases we don't know exactly. If you have a treatment, maybe your incidence is much increased, and severe or attenuated [inaudible 00:04:09]. Alpha-mannosidosis is still a new disorder, and must differentiate from Mucopolysaccharidosis.

On the other hand, the Fabry disease I think is very common. There are many discussion already in the past 20 years. Deficiency of a-Gal A, accumulation of Gb3⁵­­ or Lyso-Gb3, many other glycoprotein, which a terminal of a-Gal A, and X-chromosome. This is very important X-chromosomal inheritance. In case of this, and usually, female does not affect, but in case of Fabry, more of female also involved.
First symptom, imagine at any age. Then incidence about 1:40,000-1:60,000. But depending on the country, as you know, classical form, about 1:40,000. Recently, after the newborn screening, late onset, very high incidence. About 90% of it—actually, we carried out a newborn screening in Japan—90% are late onset. But the clinical variety, so many clinical varieties, so incidents here, 1:3,000-1:4,000, something like that. Now, using the Alpha-mannosidosis and Fabry disease as an illustrative example, we will explore these disorders.


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