On September 17, 1999, 18-year-old American Jesse Gelsinger became the first person to die as an unintended consequence of gene replacement therapy research.9,10 Jesse had partial ornithine transcarbamylase (OTC) deficiency and received an infusion of a recombinant adenoviral vector that included the OTC gene. He experienced a severe immune reaction to the vector and died 4 days after receiving the injection.10

The recombinant adenoviral vector had not been considered to pose a risk.10 However, in a preclinical trial, a rhesus monkey died after an extremely high dose of a first-generation vector.11 Furthermore, Jesse, along with one other patient, received the highest dose of an adenoviral vector to be administered up to that point (3.8 × 1013 vector particles).11 At the time of Jesse’s death, over 4000 individuals had participated in approximately 400 gene therapy clinical trials, with no other deaths attributed to a gene delivery vehicle.9

Although this death caused setbacks for gene therapy research in the US, it led to the creation of new regulatory processes for gene therapy clinical trials.9,10