Chapter 1: Introduction to Gene Directed Therapies

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, PhDI'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.