For over four decades, the aspiration of gene therapy has been to develop novel therapies with the potential to enhance human health. Recombinant AAV (rAAV), a type of gene therapy, is engineered without viral DNA and is designed to traverse cell membranes, delivering DNA cargo into a cell’s nucleus.

The Risks of Viral Delivery Systems

A recent paper published in the New England Journal of Medicine (NEJM) suggested a potential cause of death in a Duchenne muscular dystrophy (DMD) patient in 2022. The patient, 27-year-old Terry Horgan, received a high dose of rAAV-mediated gene therapy as a treatment for a rare form of DMD, a therapy sanctioned by the FDA. Unfortunately, Terry developed mild cardiac disturbances, excess pericardial fluid, and severe alveolar damage. While there were no signs of a cell-mediated immune response against the AAV delivery system, given the patient’s advanced condition, the researchers concluded that his chances of surviving the cardiopulmonary stress were minimal.

Terry Horgan was the brother of the founder of Cure Rare Disease (CRD), a non-profit biotech that funded the study and supported the FDA-sanctioned DMD trial.

The gene therapy field has faced safety challenges, with serious adverse events reported by pharma companies like Astellas Pharma. In 2021, Astellas paused its Aspiro study in x-linked myotubular myopathy due to serious adverse events and deaths. Similarly, Pfizer reported a death in its DMD trial involving an investigational gene therapy. Both Pfizer and Astellas have shared some of their study findings with the medical community.

Plans for a Safer Option

Astellas Pharma has recently announced plans, via STAT News, to develop a lower-risk therapy that can achieve the same effectiveness with lower doses, thereby minimizing the risk of severe adverse events. This new therapy aims to treat X-linked myotubular myopathy (XLMTM) safely and effectively while still delivering genes into the patient’s cells.