Investigation of the Cause of Death in a Gene-Therapy Trial

A 36-year-old woman with rheumatoid arthritis who was receiving systemic immunotherapy died from disseminated histoplasmosis while participating in a gene-therapy trial of a tumor necrosis factor α antagonist delivered through an adeno-associated viral vector delivery system and administered by intraarticular injection. A 36-year-old woman with rheumatoid arthritis who was receiving systemic immunotherapy died from disseminated histoplasmosis while participating in a gene-therapy trial of a tumor necrosis factor α antagonist. Rheumatoid arthritis is a chronic inflammatory disease that is characterized by autoimmune destruction of multiple joints, causing substantial pain, swelling, and loss of mobility. 1 TNF-α inhibitors have represented a dramatic improvement in the treatment of rheumatoid arthritis; they include the two antibodies infliximab and adalimumab, as well as etanercept, a dimeric fusion protein that combines an immunoglobulin domain with a TNF-receptor domain (TNFR:Fc). 2 , 3 Trials of TNF-α inhibitors delivered with the use of gene-therapy methods in patients with rheumatoid arthritis are increasing in number. 4 The most common vectors used in models of rheumatoid arthritis are viral vectors such as lentivirus, . . .