A pilot study of in vivo liver-directed gene transfer with an adenoviral vector in partial ornithine transcarbamylase deficiency

Institute for Human Gene Therapy and Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
Human Gene Therapy (Impact Factor: 3.62). 02/2002; 13(1):163-75. DOI: 10.1089/10430340152712719
Source: PubMed

ABSTRACT Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that has been considered as a model for liver-directed gene therapy. Current treatment has failed to avert a high mortality or morbidity from hyperammonemic coma. Restoration of enzyme activity in the liver should suffice to normalize metabolism. An E1- and E4-deleted vector based on adenovirus type 5 and containing human OTC cDNA was infused into the right hepatic artery in adults with partial OTCD. Six cohorts of three or four subjects received 1/2 log-increasing doses of vector from 2 x 10(9) to 6 x 10(11) particles/kg. This paper describes the experience in all but the last subject, who experienced lethal complications. Adverse effects included a flu-like episode and a transient rise in temperature, hepatic transaminases, thrombocytopenia, and hypophosphatemia. Humoral responses to the vector were seen in all research subjects and a proliferative cellular response to the vector developed in apparently naive subjects. In situ hybridization studies showed transgene expression in hepatocytes of 7 of 17 subjects. Three of 11 subjects with symptoms related to OTCD showed modest increases in urea cycle metabolic activity that were not statistically significant. The low levels of gene transfer detected in this trial suggest that at the doses tested, significant metabolic correction did not occur.

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    • "Hepatocytes have proved highly susceptible to transduction by a number of viral vectors (Fig. 2). Advanced studies have shown that both adenovirus and AAV vectors can be used to transduce the liver with high efficiency in vivo in animal studies (Jaffe et al., 1992; Li et al., 1993; Nathwani et al., 2006) and in clinical trials (Raper et al., 2002; Nathwani et al., 2011). No significant side effects have been reported in clinical trials for AAV. "
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    • "When the therapeutic effect can be achieved upon expression of a single gene in post‐mitotic tissue, non‐integrating vector systems are favoured. Indeed, in one of the first in vivo clinical trials, an attenuated adenovirus‐derived vector was used for the treatment of ornithine transcarbamylase deficiency (OTCD), an inborn disease of urea synthesis (Raper et al, 2002). Vector‐ and transgene‐elicited immunoreactions were initially of concern in the in vivo application of vector particles, as documented by the death of one out of the 17 subjects treated in the OTCD trial, which was caused by a massive immune reaction against the capsid of the infused adenoviral vector (Raper et al, 2003). "
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