Chapter 3: Immune Responses and Other Safety Concerns Related to Gene Therapies

Nicola Longo MD, PhD, and Mark Roberts, MDNicola Longo MD, PhDProfessor 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, USAMark Roberts, MDProfesor and Consultant Neurologist,University of Manchester, Manchester, UKResearch Lead for Adult Metabolic Medicine at Salford Care Organisation, Manchester, UKDrs. 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, MDUndoubtedly, 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.