title: Liver toxicities typically induced by first-generation adenoviral vectors can be reduced by use of E1, E2b-deleted adenoviral vectors.
abstract: Adenoviral vectors from which the E1 region has been deleted ([E1(-)] Ad) are known to induce strong immune responses after systemic delivery. In this study we have evaluated liver toxicities in mice after intravenous injection with high doses of [E1(-)] or modified [E1(-), E2b(-)] Ad vectors (both expressing the bacterial beta-galactosidase [lacZ] marker gene) in C57BL/6, BALB/c, and SCID mice. Our data demonstrate a marked reduction in maximal liver toxicities and pathologies (typically noted at 21 days postinjection) with the use of the [E1(-), E2b(-)] modified vector in all strains of mice tested. Our data also demonstrated that despite the use of the [E1(-), E2b(-)] Ad vector, significant liver toxicities were still observed. To address this issue and the fact that the lacZ gene was perceived as a foreign antigen in the immune-competent C57BL/6 and BALB/c mice, we similarly injected mice tolerant of LacZ (lacZ-TG). In contrast to our studies in C57BL/6 and BALB/c mice, LacZ-TG mice exhibited virtually no evidence of hepatotoxicity after intravenous injection with the [E1(-), E2b(-)] vector, in contrast to use of the [E1(-)] Ad vector. Our results demonstrate that the [E1(-), E2b(-)] Ad vector class can reduce liver toxicities typically ascribed to Ad vector-mediated gene transfer after transfer of a highly immunogenic or foreign gene, whereas transfer of a transgene that is perceived as nonforeign by the host can be delivered with virtually no evidence of toxicity. On the basis of a careful review of the literature, these improvements in vector safety rival those noted with other, more significantly modified Ad vectors described to date.
authors.affiliation: Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27705, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Everett
authors.forename: B L
authors.initials: BL
authors.lastname: Hodges
authors.forename: E Y
authors.initials: EY
authors.lastname: Ding
authors.forename: F
authors.initials: F
authors.lastname: Xu
authors.forename: D
authors.initials: D
authors.lastname: Serra
authors.forename: A
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000472:pathogenicity*; D017498:Adenovirus E1 Proteins / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors; D007763:Lac Operon / Q000235:genetics*; D008099:Liver / Q000473:pathology* / Q000821:virology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID
chemical_list: D017498:Adenovirus E1 Proteins