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Publications (4)14.28 Total impact

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    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.
    Human Gene Therapy 02/2002; 13(1):163-75. · 3.62 Impact Factor
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    ABSTRACT: A third-generation adenoviral vector containing recombinant human cystic fibrosis transmembrane conductance regulator (CFTR) gene was delivered by bronchoscope in escalating doses to the conducting airway of 11 volunteers with cystic fibrosis. Assessments of dose-limiting toxicity (DLT), efficiency of gene transfer, and cell-mediated and humoral immune responses to vector administration were performed. DLT, manifest by flulike symptoms and transient radiographic infiltrates, was seen at 2.1 x 10(11) total viral particles. A highly specific assay for gene transfer was developed using in situ hybridization with an oligoprobe against unique vector sequence. Detectable gene transfer was observed in harvested bronchial epithelial cells (<1%) 4 days after vector instillation, which diminished to undetectable levels by day 43. Adenovirus-specific cell-mediated T cells were induced in most subjects, although only mild increases in systemic humoral immune response were observed. These results demonstrate that gene transfer to epithelium of the lower respiratory tract can be achieved in humans with adenoviral vectors but that efficiency is low and of short duration in the native CF airway.
    Human Gene Therapy 12/1999; 10(18):2973-85. · 3.62 Impact Factor
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    ABSTRACT: Vectors based on human adenovirus (Ad) and adeno-associated virus (AAV) are being evaluated for human gene therapy. The response of the host to the vector, in terms of antigen-specific immunity, will play a substantial role in clinical outcome. We have surveyed cohorts of normal subjects and cystic fibrosis patients for pre-existing immunity to these viruses, caused by naturally acquired infections. A number of humoral and cellular assays to adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 2 (AAV2) were performed from serum and peripheral blood mononuclear cells. Virtually all subjects had Ig to Ad5 although only 55% of these antibodies neutralized virus (NAB). Approximately two of three patients demonstrated CD4+ T cells that proliferated to Ad antigens of which most were of the TH1 subset, based on cytokine secretion. A substantially different pattern of immune responses was observed to AAV2. Although virtually all patients had Ig to AAV2, most of these antibodies were not neutralizing (32% NAB) and only 5% of patients had peripheral blood lymphocytes that proliferated in response to AAV2 antigens. These studies demonstrate marked heterogeneity in pre-existing immunity to Ad5 and AAV2 in human populations. The impact of these findings on outcome following gene therapy will require further study.
    Gene Therapy 10/1999; 6(9):1574-83. · 4.20 Impact Factor
  • Pediatric Research 04/1998; 43. · 2.84 Impact Factor