Reinventing Gene Therapy?
Recent fatalities in clinical trials for gene therapies have led to greater regulatory scrutiny and concerns over safety, particularly in relation to the use of viral vectors, leading industry to question whether a potential therapeutic reinvention is needed.
The development of gene therapies has been pivotal for many patients suffering from a variety of rare and difficult-to-treat diseases, even offering curative or preventative solutions for some cases. However, given the recent concerning safety issues and fatalities that have occurred in a number of trials, there is a renewed focus on finding a suitable delivery approach that does not cause an immune response.
While the therapeutic potential of in vivo gene therapies is hugely promising, their delivery has proven to be a bit of a sticking point. In 1999, the field of in vivo gene therapy was rocked when 18-year-old trial volunteer, Jesse Gelsinger, died after being administered an experimental gene-repair treatment. Gelsinger had suffered from a catastrophic immune response to the adenovirus vector that was used as the therapy’s delivery vehicle and as a result of this tragic event, progress in the field stalled for at least a decade (1).
Since that time, in vivo gene therapy has experienced a resurgence thanks to innovations that have improved safety, such as the use of adeno-associated virus (AAV) vectors and clustered regularly interspaced short palindromic repeats (CRISPR) technology (2). Yet, despite the improvements in safety these innovations have afforded, recent adverse events have given rise to renewed uncertainty and scrutiny.
Most recently, three reported fatalities from acute liver failure post treatment have spurred an investigation by the FDA of Sarepta Therapeutics’ gene therapies. After receiving the reports of the fatalities, the agency requested a suspension in the distribution of the single-dose, AAV-based gene transfer therapy, delandistrogene moxeparvovec-rokl (Elevidys), and also a pause in clinical trials for multiple gene therapy products, including AAVrh74, to be able to perform an investigation (3). Even though the agency has, after reviewing all available safety information, recommended that distribution of Elevidys be resumed for ambulatory patients with Duchenne muscular dystrophy, it is continuing to with Sarepta to update the safety labeling on the therapy and develop a risk-mitigation approach for non-ambulatory patients (4).
A few months earlier, Rocket Pharmaceuticals also experienced setbacks with its experimental gene therapy for cardiovascular disease after a volunteer participant experienced unexpected clinical complications — capillary leak syndrome — during a clinical trial (5). The trial was voluntarily paused by the company to allow for safety investigations to be performed and has not yet, at the time of writing, been resumed.
With other late-stage trials involving in vivo gene therapies packaged and delivered via AAV also stalling or failing (6), and the unresolved issue of whether or not a patient’s antibody immune response prevents such therapies from working (2), alternative vectors are being researched. Other options under investigation include AAVs from other species or lentiviral vectors (LVVs) (2,6).
However, given the risks and complications that have been experienced with AAV delivered gene therapies, many companies are pulling back from the AAV space — Takeda, Pfizer, Roche, and, most recently, Vertex Pharmaceuticals announcing cutbacks or their departures from the field (7). The recent safety issues being a death knell in an already challenging space as the risk to benefit ratio simply becomes untenable.
These shifts in the gene therapy landscape will prove to be pivotal for many industry stakeholders and has the potential to dramatically sway investment to less risky prospects. Innovators and CDMOs that can be flexible in their capacity and capabilities to pivot to new demands for modular non-viral systems will be the future successors in the field of gene therapy.
References
Rinde, M. The Death of Jesse Gelsinger, 20 Years Later. Distillations Magazine, June 4, 2019.
Brazil, R. Gene Therapy: From Catastrophe to Cure in 20 Years. The Pharmaceutical Journal. Article, Jan. 13, 2022.
FDA. FDA Investigating Deaths Due to Acute Liver Failure Following Treatment with Sarepta’s AAVrh74 Gene Therapies. Safety Communication, July 18, 2025.
Sarepta Therapeutics. FDA Informs Sarepta that it Recommends that Sarepta Remove its Pause and Resume Shipments of ELEVIDYS for Ambulatory Individuals with Duchenne Muscular Dystrophy. Press Release, July 28, 2025.
Rocket Pharma. Rocket Pharmaceutical Provides Update on Phase II Clinical Trial of RP-A501 for Danon Disease. Press Release, May 27, 2025.
Kapadi. Gene Therapy — Related Mortality: Mechanistic Insights, Regulatory Repercussions, and the Role of Lentiviral Vectors in a Heightened Safety Landscape. Blog Post, June 11, 2025.
Lopez, I. Gene Therapy Market Shaken as Vertex Abandons AAV Technology Amid Safety Concerns and Regulatory Upheaval. Article, CTOL Digital Solutions, May 4, 2025.