One-year Expression from High-capacity Adenoviral Vectors in the brains of animals with pre-existing anti-adenoviral immunity: Clinical implications

BARCIA; JIMENEZ-DALMARONI; KROEGER; PUNTEL; RAPAPORT; LAROCQUE; KING; JOHNSON; LIU; XIONG; CANDOLFI; MONDKAR; NG; PALMER; CASTRO; LOWENSTEIN

MOLECULAR THERAPY (PRINT)

NATURE PUBLISHING GROUP

Año: 2007 p. 2154 - 2163

1525-0016

The main challenge of gene therapy is to provide longterm,efficient transgene expression. Long-term transgeneexpression from first generation adenoviral vectors (Advs)delivered to the central nervous system (CNS) is elicited inanimals not previously exposed to adenovirus (Ad). However,upon systemic immunization against Ad, transgeneexpression from a first generation Adv is abolished. HighcapacityAdvs (HC-Advs) provide sustained very longtermtransgene expression in the brain, even in animalspre-immunized against Ad. In this study, we tested thehypothesis that a HC-Adv in the brain would allow forlong-term transgene expression, for up to 1 year, in thebrain of mice immunized against Ad prior to delivery ofthe vector to the striatum. In naïve animals, the expressionof β-galactosidase from Adv or HC-Adv was sustainedfor 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-mediatedtransgene expression in the brain, even in animals thathad been immunized systemically against Ad before thedelivery of HC-Adv into the brain. This study thereforeindicates the utility of HC-Adv as a powerful gene therapyvector for chronic neurological disorders, even in patientswho had been pre-exposed to Ad prior to gene therapy.