Impact of transgene expression on drug metabolism following systemic adenoviral vector administration

Callahan, Shellie M.; Boquet, Michael P.; Xin, Ming; Brunner, Lane J.; Croyle, Maria A.

doi:10.1002/jgm.884

Cited by 18 publications

(26 citation statements)

References 44 publications

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“…A previous report described that infection of an adenovirus caused adenovirusderived hepatotoxicity (30). Therefore, we validated the condition of adenovirus infection (Fig.…”

Section: Discussionmentioning

confidence: 73%

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Akai

Hosomi

Minami

et al. 2007

Journal of Biological Chemistry

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Drug-induced hepatotoxicity is mainly caused by hepatic glutathione (GSH) depletion. In general, the activity of rodent glutathione S-transferase is 10 to 20 times higher than that of humans, which could make the prediction of drug-induced hepatotoxicity in human more difficult. ␥-Glutamylcysteine synthetase (␥-GCS) mainly regulates de novo synthesis of GSH in mammalian cells and plays a central role in the antioxidant capacity of cells. In this study, we constructed a GSH-depletion experimental rat model for the prediction of human hepatotoxicity. An adenovirus vector with short hairpin RNA against rat ␥-GCS heavy chain subunit (GCSh) (AdGCSh-shRNA) was constructed and used to knock down the GCSh. In in vitro study in H4IIE cells, a rat hepatoma cell line, GCSh mRNA and protein were significantly decreased by 80% and GSH was significantly decreased by 50% 3 days after AdGCSh-shRNA infection. In the in vivo study in rat, the hepatic GSH level was decreased by 80% 14 days after a single dose of AdGCSh-shRNA (2 ؋ 10 11 pfu/ml/ body), and this depletion continued for at least 2 weeks. Using this GSH knockdown rat model, acetaminophen-induced hepatotoxicity was shown to be significantly potentiated compared with normal rats. This is the first report of a GSH knockdown rat model, which could be useful for highly sensitive tests of acute and subacute toxicity for drug candidates in preclinical drug development.

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“…A previous report described that infection of an adenovirus caused adenovirusderived hepatotoxicity (30). Therefore, we validated the condition of adenovirus infection (Fig.…”

Section: Discussionmentioning

confidence: 73%

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Akai

Hosomi

Minami

et al. 2007

Journal of Biological Chemistry

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“…Alternatively, the nuclear localized LacZ enzyme expressed by our vectors could have toxic or detrimental effects as discussed recently thus leading to a counter-selection against transduced cells. 41 Our study reveals that not only the closely related FVs of simian and higher primates but also the distantly related FFV cannot be pseudotyped by heterologous surface glycoproteins of different origin. Even the Env protein from the human/primate FV did not allow efficient marker gene transduction, underlining the concept that highly specific Gag-Env interactions are required for proper particle assembly although other reasons cannot be formally excluded.…”

Section: Discussionmentioning

confidence: 71%

Construction and characterization of efficient, stable and safe replication-deficient foamy virus vectors

et al. 2007

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As serious side effects affected recent virus-mediated gene transfer studies, novel vectors with improved safety profiles are urgently needed. In the present study, replicationdeficient retroviral vectors based on feline foamy virus (FFV) were constructed and analyzed. The novel FFV vectors are devoid of almost the complete env gene plus the internal promoter -accessory bel gene cassette including the gene for the viral transcriptional transactivator Bel1/Tas. In these Bel1/Tas-independent vectors, expression of the lacZ (b-galactosidase) marker gene is directed by the heterologous, constitutively active human ubiquitin C promoter (ubi). Env-transcomplemented vectors have unconcentrated titers of more than 10 5 transducing units/ml.The vectors allow efficient transduction of a broad array of diverse target cells, which can be increased by repeated vector exposure. However, the number of lacZ marker gene expressing cells decreased slightly upon serial passages of the transduced cells. Vectors carrying a self-inactivating (SIN) deletion of the TATA box and most parts of the viral promoter were not rescued by wt FFV whereas those with the intact or a partially deleted promoter were readily reactivated. This finding indicates that the viral promoters are in fact non-functional, pointing to a highly advantageous safety profile of these new FFV-ubi-lacZ-SIN vectors.

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“…Betagalactosidase expression was assessed in tissue samples by histochemical staining as described previously (11). The number of virus genomes in tissue was determined by real-time PCR of genomic DNA extracts as described previously (7). Serum cytokines were assessed by ELISA (Invitrogen, BioSource International, Camarillo, CA).…”

Section: Methodsmentioning

confidence: 99%

Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

Choi

Dekker²,

Schafer

et al. 2012

Clin Vaccine Immunol

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The immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity. In vitro and in vivo assays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 ؋ 10

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Impact of transgene expression on drug metabolism following systemic adenoviral vector administration

Cited by 18 publications

References 44 publications

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Knock Down of γ-Glutamylcysteine Synthetase in Rat Causes Acetaminophen-induced Hepatotoxicity

Construction and characterization of efficient, stable and safe replication-deficient foamy virus vectors

Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

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