Understanding the Risks of Gene Transfer Therapies Can Improve Safety of Patients with Neuromuscular Disorders   

While gene replacement therapies have expanded the armamentarium for the treatment of neuromuscular disorders (NMDs), these novel interventions may sometimes result in unwanted outcomes. Specialists in pediatric NMDs discussed the risks and possible adverse events associated with different types of gene therapies, their delivery mechanisms, and immune system reactions, in a panel at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in Orlando, Florida.

Russell Butterfield, MD, PhD, an Associate Professor in the Departments of Neurology and Pediatrics at the University of Utah, noted that the vectors used to deliver gene therapies carry inherent risks that cannot be overlooked. “These risks are based both on the innate and adaptive immune response to the therapy, and that can include an immune response to the capsid or an immune response to the transgene protein,” Butterfield said.

Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of many NMDs, including Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). While AAV-based gene delivery has been shown to be highly effective, product-related impurities and dosing issues determine the impact of the therapies. Additionally, host-related factors, such as the patients’ immune systems and their health at the time of the infusion, also contribute to potential adverse events.

Real-world data from the RESTORE registry have identified common adverse events in patients with SMA treated with onasemnogene abeparvovec (OA), including hepatotoxicity, transient thrombocytopenia, cardiac adverse events, and thrombotic microangiopathy (TMA).

Butterfield noted that adverse events associated with AAV-mediated therapies tend to follow predictable timelines. Common manifestations in the first days after the gene transfer include nausea and vomiting. While these symptoms are easy to manage, in some cases, they can signal myocardial injury, which can progress to heart failure and death. Mild troponin elevation is common in patients treated with AAV-mediated therapies. However, clinicians should be on high alert and anticipate any major adverse events. TMA, which is also relatively common in multiple AAV platforms, manifests around the end of the first week post-gene transfer. Clinical signs include decreased hematocrit and platelet levels, followed by decreased renal function. If not recognized early, TMA can lead to renal failure.

Data from DMD registries suggest that acute liver injury is the most common adverse event observed 4 to 6 weeks after gene transfer. “Clinical symptoms are not always present, so laboratory monitoring is really important to anticipate the possibility of adverse events,” Butterfield cautioned. Management of patients with adverse events typically includes hospitalization and administration of intravenous corticosteroids.

“Gene therapy is safe like chemotherapy,” Butterfield added. “It is safe for the right patient, at the right time, with the right people following up. We get these excellent results, but the potential for adverse events is high. Early close surveillance is critical.” Steps for optimizing patient safety include understanding the combination of factors specific to each patient and each therapy, assessing baseline cardiac function beyond ejection fraction, and developing best practices for the prophylaxis and treatment of adverse events.

Richard Finkel, MD, who treats children with NMDs at St. Jude Children’s Research Hospital in Memphis, Tennessee, pointed out that some risks associated with AAV-mediated gene transfer therapies may not be known at the time of administration.

“With gene therapy, we are struggling to find equipoise,” Finkel said. “We are trying to find that right balance between safety and risks, as we identify them, and efficacy. Preclinical data are helpful but not entirely predictive of risk profile in humans.”

Post-marketing studies play an important part in ensuring patient safety because the findings of clinical trials also have limitations in predicting safety profiles. TMA, which is a common adverse event in patients with SMA treated with OA, was recognized as such only after regulatory approval and was not originally identified as a potential risk in clinical trials. In some cases, it may be challenging to determine if a side effect is caused by the therapy or is a result of the progression of disease, or a combination of both.

“We’re not sure yet that we have the full picture and we can’t let our guard down,” the speaker said. Data from patient registries continue to reveal previously unknown adverse events, like necrotizing enterocolitis, which was recently reported in two infants treated with OA.

“Despite these words of caution, AAV vectors for gene transfers can be highly effective, even when administered in a high dose, but there is a narrow therapeutic window between getting efficacy and avoiding toxicity,” Finkel concluded. Given the limitations of preclinical models and clinical trial results, clinicians, institutions, and manufacturers have the responsibility of reporting adverse events and setting up post-marketing registries to share findings and mitigation strategies.