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Production of Genetically Engineered Golden Syrian Hamsters by Pronuclear Injection of the CRISPR/Cas9 Complex
Published on: January 9, 2018
Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir
Iulia Diaconu1, Vincenzo Cerullo, Sophie Escutenaire
1Cancer Gene Therapy Group, Molecular Cancer Biology Program & Transplantation Laboratory & Haartman Institute & Finnish Institute for Molecular Medicine, University of Helsinki, Haartmaninkatu 8, Helsinki, Finland.
Background:
Adenoviruses can cause severe toxicity in children and in immunocompromised adults, and therefore a means to abrogate replication would be useful. With regard to cancer treatment, replication competent oncolytic adenoviruses have been safe in humans, although their efficacy has been variable. Therefore, more effective agents are now entering clinical testing and, consequently, replication-associated side effects remain a concern. Preclinical analysis of replication related toxicity has been hampered by a lack of permissive models. Therefore, it has been difficult to study modulation of human adenovirus replication in immune competent animals.
Methods:
We investigated four different hamster carcinoma cell lines for transduction and cell killing potency in vitro and in vivo. Gene transfer was assessed using replication-deficient adenoviruses expressing luciferase. Cell killing was studied in vitro and in vivo using an oncolytic adenovirus that kills tumor cells by viral replication. After the most promising animal model had been selected, abrogation of virus replication was assessed in vitro and in vivo using a TCID(50) assay.
Results:
The results obtained suggest wild-type adenovirus replication in all four tested Syrian hamster cell lines and also normal organs. Virus replication could be abrogated with chlorpromazine, cidofovir and cytosine arabinoside, and the effect occurred subsequent to nuclear delivery of the viral genome. Attenuation of virus replication also was seen in vivo both in tumors and the liver.
Conclusions:
Syrian hamsters may comprise a valuable immune competent model for evaluating anti-adenoviral drugs. Furthermore, chlorpromazine or cidofovir might be useful in case of adenovirus replication-associated symptoms in humans.
Insights
Syrian hamsters provide a new immune-competent model for studying adenovirus replication and testing antiviral drugs. Chlorpromazine and cidofovir effectively reduced adenovirus replication in preclinical models.
Area of Science:
- Virology
- Oncolytic Virotherapy
- Preclinical Animal Models
Background:
- Adenoviruses cause significant toxicity in children and immunocompromised adults.
- Oncolytic adenoviruses show variable efficacy and potential replication-associated side effects in cancer treatment.
- Lack of permissive immune-competent animal models hinders preclinical analysis of adenovirus replication.
Purpose of the Study:
- To evaluate Syrian hamster carcinoma cell lines as a model for adenovirus transduction and oncolysis.
- To assess the efficacy of antiviral drugs in abrogating adenovirus replication in vitro and in vivo.
Main Methods:
- Investigated four hamster carcinoma cell lines for transduction and cell killing using replication-deficient and oncolytic adenoviruses.
- Assessed gene transfer with luciferase-expressing adenoviruses.
- Evaluated virus replication abrogation using TCID(50) assays in vitro and in vivo.
Main Results:
- Wild-type adenovirus replicated in all tested Syrian hamster cell lines and normal organs.
- Chlorpromazine, cidofovir, and cytosine arabinoside abrogated adenovirus replication post-nuclear genome delivery.
- Replication attenuation was observed in vivo in tumors and liver.
Conclusions:
- Syrian hamsters represent a valuable immune-competent model for anti-adenoviral drug evaluation.
- Chlorpromazine and cidofovir show potential for managing adenovirus replication-associated symptoms in humans.
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