In a heart-wrenching turn of events, a recent paper in The New England Journal of Medicine unravels the possible cause behind the untimely demise of a 27-year-old Duchenne muscular dystrophy (DMD) patient in 2022. Terry Horgan’s tragic death has been tentatively linked to an unexpected immune reaction triggered by the high dosage of recombinant adeno-associated virus (AAV) used to administer an investigational CRISPR-based therapy.
November 2022 marked the loss of Terry Horgan, who had bravely volunteered for an FDA-approved study exploring a novel CRISPR-based therapy tailored to his rare form of DMD.
According to the recent report, Terry experienced mild cardiac dysfunction and pericardial effusion following the CRISPR treatment, later descending into acute respiratory distress syndrome (ARDS) and cardiac arrest.
Post-mortem examinations unveiled severe diffuse alveolar damage, but surprisingly, only minimal traces of the transgene therapy were found in the liver. Equally perplexing, there were no signs of immune responses, either humoral or cell-mediated, targeting the AAV used for therapy delivery or the transgene product itself, as revealed by the study’s authors.
Collectively, these findings suggest that Terry’s tragic passing may have resulted from an innate immune reaction spurred by the substantial dose of recombinant AAV used for gene therapy delivery, exacerbated by the advanced stage of his condition. This advanced stage could have limited his physiological resilience and ability to withstand the cardiopulmonary stress induced by the gene therapy’s toxic effects.
It’s worth noting that this NEJM study was funded by Cure Rare Disease (CRD), a nonprofit biotech organization that also supported the FDA-sanctioned DMD trial. Heartbreakingly, Terry Horgan was the brother of CRD’s founder.
Patient fatalities have, regrettably, been a recurrent challenge in investigational gene therapies for rare diseases. In a troubling incident in September 2021, Astellas Pharma paused its Aspiro study due to serious adverse events and mortalities linked to the AAV-based investigational gene therapy AT132 in X-linked myotubular myopathy. Ultimately, four patients lost their lives during the trial.
Pfizer also encountered safety concerns in December 2021, when one participant in its DMD trial passed away after receiving the investigational gene therapy PF-06939926, which also employed an AAV delivery system. In response, Pfizer halted screening and dosing in the study.
While both Astellas and Pfizer have shared some of their findings from these trials at medical conferences, they have yet to publish comprehensive investigations into these tragic incidents, leaving many questions unanswered in the realm of gene therapy safety.”