INGN 007, an oncolytic adenovirus vector, replicates in Syrian hamsters but not mice: comparison of biodistribution studies

Bai, Ying; Tóth, Károly; Spencer, Jacqueline F.; Meyer, J; Tollefson, Ann E.; Patra, Debabrata; Dhar, Debanjan; Shashkova, Elena V.; Kuppuswamy, Mohan; Doronin, Konstantin; Thomas, Maria; Zumstein, Louis; Wold, William S.M.; Lichtenstein, Drew L.

doi:10.1038/cgt.2009.6

Cited by 48 publications

(53 citation statements)

References 52 publications

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“…In summary, VCN-01 toxicology data obtained in the preclinical studies are similar to the previously described for ICOVIR-15, ICOVIR-15K, and ICOVIR-17 (12,21) and detected alterations match with the most common toxicity events reported after systemic administration of adenoviruses in clinical trials (35)(36)(37)41). Biodistribution studies were consistent with the toxicology pattern, with highest levels of viral genomes in the liver at early time points, in agreement with previous reports (32,(42)(43)(44)(45). However, at later time points only residual traces of viral DNA were observed in liver as well as in other nontarget organs.…”

Section: Discussionsupporting

confidence: 89%

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

Rodríguez-García

Giménez-Alejandre

Rojas

et al. 2015

Clinical Cancer Research

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Purpose: Tumor targeting upon intravenous administration and subsequent intratumoral virus dissemination are key features to improve oncolytic adenovirus therapy. VCN-01 is a novel oncolytic adenovirus that combines selective replication conditional to pRB pathway deregulation, replacement of the heparan sulfate glycosaminoglycan putative-binding site KKTK of the fiber shaft with an integrin-binding motif RGDK for tumor targeting, and expression of hyaluronidase to degrade the extracellular matrix. In this study, we evaluate the safety and efficacy profile of this novel oncolytic adenovirus.Experimental Design: VCN-01 replication and potency were assessed in a panel of tumor cell lines. VCN-01 tumor-selective replication was evaluated in human fibroblasts and pancreatic islets. Preclinical toxicity, biodistribution, and efficacy studies were conducted in mice and Syrian hamsters.Results: Toxicity and biodistribution preclinical studies support the selectivity and safety of VCN-01. Antitumor activity after intravenous or intratumoral administration of the virus was observed in all tumor models tested, including melanoma and pancreatic adenocarcinoma, both in immunodeficient mice and immunocompetent hamsters.Conclusions: Oncolytic adenovirus VCN-01 characterized by the expression of hyaluronidase and the RGD shaft retargeting ligand shows an efficacy-toxicity prolife in mice and hamsters by intravenous and intratumoral administration that warrants clinical testing.

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Section: Discussionsupporting

confidence: 89%

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

Rodríguez-García

Giménez-Alejandre

Rojas

et al. 2015

Clinical Cancer Research

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“…in C57BL/6N mice for analysis of toxicity 28 and biodistribution. 29 INGN 007 was detectable in the bone marrow from days 2 to 92, but caused no bone marrow pathology (normal erythrocyte numbers, hematocrit, hemoglobin, and red cell distribution width), consistent with Ad5-GUCY2C-PADRE bone marrow distribution without toxicity. Interestingly, Ad5 has been shown to interact with neutrophils via a novel mechanism, independent of the coxsackievirus adenovirus receptor (CAR) and the capsid RGD motifs.…”

Section: Discussionmentioning

confidence: 55%

Preclinical Evaluation of a Replication-Deficient Recombinant Adenovirus Serotype 5 Vaccine Expressing Guanylate Cyclase C and the PADRE T-helper Epitope

Snook

Baybutt

Hyslop

2016

Human Gene Therapy Methods

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“…All samples from a given experiment were processed at the same time. Adenovirus DNA was amplified with primers specific for the adenovirus E3 region (71). The reference gene encoding TATA box binding protein (TBP) was amplified with forward primer 5=-GATGCCTTATGGCACTGGAC-3= and reverse primer 5=-GCCTTTGTTGCTCTTCCAAA-3= (gifts from Lucy Osborne).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Adenovirus Replication by Cardiotonic Steroids

Grosso

Stoilov

Lingwood

et al. 2017

J Virol

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The dependence of adenovirus on the host pre-RNA splicing machinery for expression of its complete genome potentially makes it vulnerable to modulators of RNA splicing, such as digoxin and digitoxin. Both drugs reduced the yields of four human adenoviruses (HAdV-A31, -B35, and -C5 and a species D conjunctivitis isolate) by at least 2 to 3 logs by affecting one or more steps needed for genome replication. Immediate early E1A protein levels are unaffected by the drugs, but synthesis of the delayed protein E4orf6 and the major late capsid protein hexon is compromised. Quantitative reverse transcription-PCR (qRT-PCR) analyses revealed that both drugs altered E1A RNA splicing (favoring the production of 13S over 12S RNA) early in infection and partially blocked the transition from 12S and 13S to 9S RNA at late stages of virus replication. Expression of multiple late viral protein mRNAs was lost in the presence of either drug, consistent with the observed block in viral DNA replication. The antiviral effect was dependent on the continued presence of the drug and was rapidly reversible. RIDK34, a derivative of convallotoxin, although having more potent antiviral activity, did not show an improved selectivity index. All three drugs reduced metabolic activity to some degree without evidence of cell death. By blocking adenovirus replication at one or more steps beyond the onset of E1A expression and prior to genome replication, digoxin and digitoxin show potential as antiviral agents for treatment of serious adenovirus infections. Furthermore, understanding the mechanism(s) by which digoxin and digitoxin inhibit adenovirus replication will guide the development of novel antiviral therapies.IMPORTANCE Despite human adenoviruses being a common and, in some instances, life-threating pathogen in humans, there are few well-tolerated therapies. In this report, we demonstrate that two cardiotonic steroids already in use in humans, digoxin and digitoxin, are potent inhibitors of multiple adenovirus species. A synthetic derivative of the cardiotonic steroid convallotoxin was even more potent than digoxin and digitoxin when tested with HAdV-C5. These drugs alter the cascade of adenovirus gene expression, acting after initiation of early gene expression to block viral DNA replication and synthesis of viral structural proteins. These findings validate a novel approach to treating adenovirus infections through the modulation of host cell processes.

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INGN 007, an oncolytic adenovirus vector, replicates in Syrian hamsters but not mice: comparison of biodistribution studies

Cited by 48 publications

References 52 publications

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

Safety and Efficacy of VCN-01, an Oncolytic Adenovirus Combining Fiber HSG-Binding Domain Replacement with RGD and Hyaluronidase Expression

Preclinical Evaluation of a Replication-Deficient Recombinant Adenovirus Serotype 5 Vaccine Expressing Guanylate Cyclase C and the PADRE T-helper Epitope

Suppression of Adenovirus Replication by Cardiotonic Steroids

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