Nuria Morral

School of Medicine, Medical & Molecular Genetics

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Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors

Lucio Pastore; Nuria Morral; Heshan Zhou; Racel Garcia; Robin J. Parks; Stefan Kochanek; Frank L. Graham; Brendan Lee; Arthur L. Beaudet (Profiled Author: Nuria Morral)

Human Gene Therapy. 1999;10(11):1773-1781.

Previous studies using adenoviral (Ad) vectors expressing human α 1- antitrypsin (hAAT) under the control of ubiquitous promoters (RSV, mPGK) elicited the production of antibodies to hAAT in some mouse strains (C3H/HeJ and BALB/c) but not in others (C57BL/6J). In contrast, when a helper- dependent Ad vector (AdSTK109) with all viral coding sequences deleted and expressing hAAT from human genomic DNA with the endogenous promoter was used, C3H/HeJ mice failed to develop antibodies and demonstrated long-term expression. These results suggested that promoter choice and/or properties of the vector itself might influence the host immune response to the transgene product. Direct comparison of first-generation vectors expressing the hAAT cDNA from a ubiquitous mouse PGK promoter rather than from a liver-specific mouse albumin promoter demonstrated that an antibody response to hAAT occurred with the mPGK promoter but not with the albumin promoter in C3H/HeJ mice. As expected, neither vector elicits an antibody response in C57BL/6J mice. Coinjection of the two first-generation vectors containing the mPGK and albumin promoter in C3H/HeJ mice induced an antibody response with resulting loss of detectable hAAT from the sera of the injected mice in 3-4 weeks. From these data, we conclude that under certain conditions, the choice of promoter with its associated liver-specific expression can modulate the host immune response to the transgene independent of viral backbone.

PMID: 10446917    

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