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.