Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer
Introduction
Among diseases considered for gene therapy, single gene defects have been thought to be among the most approachable targets [1]. In concert with this approach we investigated the use of liver directed adenovirus gene transfer in ornithine transcarbamylase (OTC)1 deficiency, an x-linked inborn error of urea synthesis. The rationale for this study was that current treatment of OTC deficiency has failed to avert a high mortality and morbidity from hyperammonemic coma, especially in hemizygous males [2]; and restoration of enzyme activity in a single, accessible organ, the liver, should suffice to normalize metabolism [as evidenced by the utility of liver transplantation in this disorder [3]].
In a series of preclinical studies we and others demonstrated effective transduction and expression of hepatocytes following adenovirus gene transfer [4], [5], correction of the metabolic defect in OTC deficient sparse fur mice [6], [7], and an acceptable safety profile in mice and non-human primates [8], [9], [10]. Initially, the relative efficacy of various adenovirus constructs containing the OTC transgene was tested in the mouse and in human hepatocytes [7]. Decreased immunogenicity, improved safety and prolonged transgene expression were noted in vectors deleted in both E1 and E4 [11], [12], [13], [14]. Normalization of biochemical function and prevention of neurological dysfunction following an ammonia load were demonstrated following adenovirus OTC gene transfer in the sparse fur mouse [9]. Safety at the proposed pilot study doses of the E1 and E4 deleted vectors (2 × 109–6 × 1011 particles/kg) and absence of germ-line transmission of transgene were demonstrated in mice and baboons [15], [16]. Using E4 intact adenovirus vectors in rhesus monkeys, a dose of 5 × 1012 particles/kg was well tolerated, while a dose of 1013 particles/kg was associated with severe toxicity [16]. Vector readministration in monkeys previously dosed did not appear to increase toxicity [10].
Based on the supportive preclinical studies, we proceeded with a pilot trial of gene transfer in clinically stable adults with partial OTC deficiency. This represented one of the first two trials of intravascular gene transfer [17], [18].
Section snippets
Clinical trial
Details of the trial and the results obtained in the first 17 dosed subjects have been previously reported [18]. Briefly, a pilot study was designed to assess the safety of escalating doses of a recombinant adenovirus vector expressing the human OTC transgene. Vector was administered by infusion into the right hepatic artery. This protocol was approved by the Institutional Review Boards of the University of Pennsylvania, Children’s Hospital of Philadelphia and Children’s National Medical
Clinical summary
Jesse Gelsinger (referred to in the text as subject OTC.019) was diagnosed as having partial OTC deficiency at 30 months of age following an episode of vomiting, seizures, and coma associated with hyperammonemia. He was subsequently found to have a unique mutation leading to mosaicism for OTC deficiency [19]. Despite treatment with a low protein diet and alternate pathway therapy [20], he experienced multiple episodes of clinically symptomatic hyperammonemia. This culminated in an episode of
Unanticipated clinical sequelae
The timing of vector administration with the onset of clinical illness suggests that vector administration resulted in the clinical outcome in this patient. In particular, organ failure in lung and bone marrow was notable. The proximate cause of death was acute respiratory distress syndrome (ARDS), which has a reported mortality rate of 36% [21]. The ARDS developed in the context of apparent activation of systemic inflammation complicated by multi-organ failure. The lungs showed neutrophilic
Acknowledgements
This clinical trial was supported by P30-DK47757, P01-HD32649, P30HD40677, FD-R 001529, and philanthropic sources. Dr. Wilson previously received support from Genovo, Inc., a company in which he holds equity. Technical assistance was provided by the Immunology and Cell Morphology Cores of the Division of Medical Genetics in the Department of Medicine at the University of Pennsylvania. The authors acknowledge Randall A. Heidenreich, M.D., Department of Pediatrics, University of Arizona, Tucson,
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