One-year expression from high-capacity adenoviral vectors in the brains of animals with pre-existing anti-adenoviral immunity: Clinical implications

Carlos Barcia, Maximiliano Jimenez-Dalmaroni, Kurt M. Kroeger, Mariana Puntel, Alison J. Rapaport, Daniel Larocque, Gwendalyn D. King, Stephen A. Johnson, Chunyan Liu, Weidong Xiong, Marianela Candolfi, Sonali Mondkar, Philip Ng, Donna Palmer, Maria G. Castro, Pedro R. Lowenstein

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

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 β-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.

Original languageEnglish (US)
Pages (from-to)2154-2163
Number of pages10
JournalMolecular Therapy
Volume15
Issue number12
DOIs
StatePublished - Dec 2007
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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