Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions

Ben Gary Harvey, Jaman Maroni, Kelley A. O’donoghue, Karen W. Chu, Jolene C. Muscat, Allison L. Pippo, Connie E. Wright, Charleen Hollmann, Juan P. Wisnivesky, Paul D. Kessler, Henrik S. Rasmussen, Todd K. Rosengart, Ronald G. Crystal

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Abstract

To help define the safety profile of the use of adenovirus (Ad) gene transfer vectors in humans, this report summarizes our experience since April 1993 of the local administration of E12/E3Ad vectors to humans using low (<109particle units) or intermediate (109-1011particle units) doses. Included in the study are 90 individuals and 12 controls, with diverse comorbid conditions, including cystic fibrosis, colon cancer metastatic to liver, severe coronary artery disease, and peripheral vascular disease, as well as normals. These individuals received 140 different administrations of vector, with up to seven administrations to a single individual. The vectors used include three different transgenes (human cystic fibrosis transmembrane conductance regulator cDNA, E. coli cytosine deaminase gene, and the human vascular endothelial growth factor 121 cDNA) administered by six different routes (nasal epithelium, bronchial epithelium, percutaneous to solid tumor, intradermal, epicardial injection of the myocardium, and skeletal muscle). The total population was followed for 130.4 patient-years. The study assesses adverse events, common laboratory tests, and long-term follow-up, including incidence of death or development of malignancy. The total group incidence of major adverse events linked to an Ad vector was 0.7%. There were no deaths attributable to the Ad vectors per se, and the incidence of malignancy was within that expected for the population. Overall, the observations are consistent with the concept that local administration of low and intermediate doses of Ad vectors appears to be well tolerated.

Original languageEnglish
Pages (from-to)15-63
Number of pages49
JournalHuman gene therapy
Volume13
Issue number1
DOIs
Publication statusPublished - 1 Jan 2002

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Harvey, B. G., Maroni, J., O’donoghue, K. A., Chu, K. W., Muscat, J. C., Pippo, A. L., Wright, C. E., Hollmann, C., Wisnivesky, J. P., Kessler, P. D., Rasmussen, H. S., Rosengart, T. K., & Crystal, R. G. (2002). Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Human gene therapy, 13(1), 15-63. https://doi.org/10.1089/10430340152712638