The dose makes the poison: Mechanisms of cytotoxicity of high-dose AAV vectors

In the year 1538, the Swiss physician Paracelsus wrote, “All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison.”1 Recombinant adeno-associated virus (rAAV) vectors have long been known for their favorable safety profile. However, in recent years, as manufacturing technology improved, the maximum feasible doses of rAAV increased and a small percentage of patients have experienced severe and even fatal toxicities from rAAV gene therapy. Several different toxicity syndromes have emerged, including hepatotoxicity, thrombotic microangiopathy (TMA), thrombocytopenia, myocarditis, acute respiratory distress syndrome, and hemophagocytic lymphohistiocytosis (HLH).