TY - JOUR
T1 - One-year expression from high-capacity adenoviral vectors in the brains of animals with pre-existing anti-adenoviral immunity
T2 - Clinical implications
AU - Barcia, Carlos
AU - Jimenez-Dalmaroni, Maximiliano
AU - Kroeger, Kurt M.
AU - Puntel, Mariana
AU - Rapaport, Alison J.
AU - Larocque, Daniel
AU - King, Gwendalyn D.
AU - Johnson, Stephen A.
AU - Liu, Chunyan
AU - Xiong, Weidong
AU - Candolfi, Marianela
AU - Mondkar, Sonali
AU - Ng, Philip
AU - Palmer, Donna
AU - Castro, Maria G.
AU - Lowenstein, Pedro R.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke [grant nos. 1 RO1 NS 42893.01, U54 NS045309-01, and 1R21 NS047298-01] (P.R.L.), and The Bram and Elaine Goldsmith Chair In Gene Therapeutics (P.R.L.); National Institutes of Health/National Institute of Neurological Disorders and Stroke [grant no. 1R01 NS44556.01], National Institute of Diabetes and Digestive and Kidney Diseases [grant no. 1 RO3 TW006273-01] (M.G.C.), and The Medallion Chair in Gene Therapeutics (M.G.C.); and The Linda Tallen and David Paul Kane Foundation Annual Fellowship (M.G.C., P.R.L.). P.N. is supported by grant no. R01DK067324. We also thank the generous funding our Institute receives from the Board of Governors at Cedars Sinai Medical Center. The authors have no conflicting financial interests. We thank the support and academic leadership of Shlomo Melmed and David Meyer (Cedars-Sinai Medical Center and David Geffen School of Medicine).
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
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U2 - 10.1038/sj.mt.6300305
DO - 10.1038/sj.mt.6300305
M3 - Article
C2 - 17895861
AN - SCOPUS:36348929875
VL - 15
SP - 2154
EP - 2163
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 12
ER -