title: Preexisting antiadenoviral immunity is not a barrier to efficient and stable transduction of the brain, mediated by novel high-capacity adenovirus vectors.
abstract: The utility of first-generation adenovirus vectors for long-term gene transfer in humans is limited by preexisting antiadenoviral immunity. We demonstrate here that new-generation high-capacity adenovirus vectors (HC-Ads) can efficiently transduce the brain and mediate stable transgene expression for at least 2 months, even in the presence of a preexisting antiadenoviral immune response. First-generation vector-mediated transduction was almost completely abolished in preimmunized animals within 60 days of the vector injection. Levels of HC-Ad-mediated transduction by 3 days postinjection were not significantly affected by preimmunization, were reduced within 14 days to 56% of those levels seen in nonimmunized animals, and remained stable until day 60 postinjection. Acute brain inflammation elicited by the HC-Ad vector injection was more transient, and was reduced in intensity compared with brain inflammation elicited by the first-generation vector injection in immunized animals. Inflammation was significantly higher in all immunized animals than in nonimmunized animals. Our results show that preexisting antiadenoviral immunity does not significantly reduce initial HC-Ad-mediated infection of the brain and is not a barrier to stable HC-Ad vector-mediated transduction of the CNS. Although input HC-Ad capsid proteins injected into the brain may contain transient targets for a brain-infiltrating cellular adenovirus-specific immune response, this fails to eliminate transgene expression. Thus HC-Ads show promise for gene therapy of chronic brain disease.
authors.affiliation: Molecular Medicine and Gene Therapy Unit, University of Manchester, Manchester M13 9PT, UK.
authors.forename: C E
authors.initials: CE
authors.lastname: Thomas
authors.forename: G
authors.initials: G
authors.lastname: Schiedner
authors.forename: S
authors.initials: S
authors.lastname: Kochanek
authors.forename: M G
authors.initials: MG
authors.lastname: Castro
authors.forename: P R
authors.initials: PR
authors.lastname: Lowenstein
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics*; D007106:Immune Sera / Q000276:immunology; D007114:Immunization; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D009500:Neutralization Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics* / Q000276:immunology
chemical_list: D007106:Immune Sera