Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer

• Published in: Molecular genetics and metabolism Vol. 80; no. 1; pp. 148 - 158
• Main Authors: Raper, Steven E, Chirmule, Narendra, Lee, Frank S, Wivel, Nelson A, Bagg, Adam, Gao, Guang-ping, Wilson, James M, Batshaw, Mark L
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2003
• Subjects: Adenoviridae - genetics; Adenovirus; Adenovirus E1 Proteins - genetics; Adenovirus E4 Proteins - genetics; Adolescent; Gene therapy; Gene transfer; Genetic Therapy; Genetic Vectors - genetics; Hepatocytes - enzymology; Hepatocytes - virology; Humans; Interleukin-10 - blood; Interleukin-6 - blood; Male; Ornithine Carbamoyltransferase - genetics; Ornithine Carbamoyltransferase Deficiency Disease - genetics; Ornithine Carbamoyltransferase Deficiency Disease - therapy; Ornithine transcarbamylase; Ornithine transcarbamylase deficiency; Systemic inflammatory response syndrome; Systemic Inflammatory Response Syndrome - etiology; Systemic Inflammatory Response Syndrome - virology; Tumor Necrosis Factor-alpha - chemistry; Urea cycle disorder; Systemic inflammatory response syndrome; Gene transfer; Adenovirus; Ornithine transcarbamylase deficiency; Urea cycle disorder; Gene therapy; Ornithine transcarbamylase
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2003.08.016

We report the death of an 18-year-old male with partial ornithine transcarbmaylase (OTC) deficiency who participated in a pilot (safety) study of gene therapy. The vector used for this trial was based on human adenovirus type 5, deleted in E1 and E4, and contained human OTC cDNA. It was infused into the right hepatic artery at a dose of 6 × 10 11 particles/kg. Approximately 18 h. following gene transfer the subject was noted to have altered mental status and jaundice—clinical signs not seen in any of the first 17 subjects in this study. Subsequently, his clinical course was marked by systemic inflammatory response syndrome, biochemically detectable disseminated intravascular coagulation, and multiple organ system failure, leading to death 98 h following gene transfer. Post-mortem examination was consistent with the clinical course, and vector DNA sequences were readily detectable in most tissues. The subject had high serum levels of IL-6 and IL-10 but normal TNFα immediately after infusion of the vector. This experience points to the limitations of animal studies in predicting human responses, the steep toxicity curve for replication defective adenovirus vectors, substantial subject-to-subject variation in host responses to systemically administered vectors, and the need for further study of the immune response to these vectors.