title: One-year expression from high-capacity adenoviral vectors in the brains of animals with pre-existing anti-adenoviral immunity: clinical implications.
abstract: The main challenge of gene therapy is to provide long-term, efficient transgene expression. Long-term transgene expression from first generation adenoviral vectors (Advs) delivered to the central nervous system (CNS) is elicited in animals not previously exposed to adenovirus (Ad). However, upon systemic immunization against Ad, transgene expression from a first generation Adv is abolished. High-capacity Advs (HC-Advs) provide sustained very long-term transgene expression in the brain, even in animals pre-immunized against Ad. In this study, we tested the hypothesis that a HC-Adv in the brain would allow for long-term transgene expression, for up to 1 year, in the brain of mice immunized against Ad prior to delivery of the vector to the striatum. In naïve animals, the expression of beta-galactosidase from Adv or HC-Adv was sustained for 1 year. In animals immunized prior to vector delivery, expression from a first generation Adv was abolished. These results point to a very long-term HC-Adv-mediated transgene expression in the brain, even in animals that had been immunized systemically against Ad before the delivery of HC-Adv into the brain. This study therefore indicates the utility of HC-Adv as a powerful gene therapy vector for chronic neurological disorders, even in patients who had been pre-exposed to Ad prior to gene therapy.
authors: Board of Governors' Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
authors: Carlos
authors: C
authors: Barcia
authors: Maximiliano
authors: M
authors: Jimenez-Dalmaroni
authors: Kurt M
authors: KM
authors: Kroeger
authors: Mariana
authors: M
authors: Puntel
authors: Alison J
authors: AJ
authors: Rapaport
authors: Daniel
authors: D
authors: Larocque
authors: Gwendalyn D
authors: GD
authors: King
authors: Stephen A
authors: SA
authors: Johnson
authors: Chunyan
authors: C
authors: Liu
authors: Weidong
authors: W
authors: Xiong
authors: Marianela
authors: M
authors: Candolfi
authors: Sonali
authors: S
authors: Mondkar
authors: Philip
authors: P
authors: Ng
authors: Donna
authors: D
authors: Palmer
authors: Maria G
authors: MG
authors: Castro
authors: Pedro R
authors: PR
authors: Lowenstein
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000276:immunology / Q000378:metabolism*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009500:Neutralization Tests; D016133:Polymerase Chain Reaction
chemical_list: D017931:DNA Primers