Chapter 1: Lysosomal Disorders and the Potential for Gene Therapies
17.12.2025
0:00
3:34
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.
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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