Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions.
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 E1(-)/E3(-) Ad vectors to humans using low (<10(9) particle units) or intermediate (10(9)-10(11) particle 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.
Harvey
Ben-Gary
BG
Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Maroni
Jaman
J
O'Donoghue
Kelley A
KA
Chu
Karen W
KW
Muscat
Jolene C
JC
Pippo
Allison L
AL
Wright
Connie E
CE
Hollmann
Charleen
C
Wisnivesky
Juan P
JP
Kessler
Paul D
PD
Rasmussen
Henrik S
HS
Rosengart
Todd K
TK
Crystal
Ronald G
RG
D000260:Adenoviruses, Human / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003110:Colonic Neoplasms / Q000628:therapy*; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000628:therapy*; D003550:Cystic Fibrosis / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D043525:Cytosine Deaminase; D004333:Drug Administration Routes; D016228:Endothelial Growth Factors / Q000235:genetics; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D008222:Lymphokines / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009700:Nucleoside Deaminases / Q000235:genetics; D016491:Peripheral Vascular Diseases / Q000628:therapy*; D012449:Safety; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C505032:CFTR protein, human; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase