Journal article
Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT, v 28
09 Mar 2023
PMID: 36700123
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self -amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and bio-distribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningi-tis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand -spe-cific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident mac-rophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.
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Details
- Title
- Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication
- Publication Details
- MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT, v 28
- Publisher
- CELL PRESS; CAMBRIDGE
- Grant note
- The authors would like to acknowledge Patrik Erlmann and col-leagues at ViraTherapeutics GmBH for providing seed viruses and sharing baseline protocols for propagation and titration, and also for helpful discussions during research conceptualization. We would like to acknowledge Sharad Sharma, Alison Johnson, Cedric Chemi-nay, Karol Budzik, and Michael Franti for helpful discussions and feedback. In addition, we would like to thank Radcliffe Fullerton, Anthony Hagerty, Tiana Lungo, Rene Roman, and Danielle Seaman for excellent technical assistance. We would like to thank Nanoimaging Services for performing electron microscopy experiments. Finally, we would like to thank Boehringer Ingelheim Animal Resources and their veterinary staff for professional animal husbandry and per-forming additional health checks to ensure the welfare of the research animals. Illustrations were created at Biorender.com . This work is funded entirely by BIPI.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:001058381900001
- Scopus ID
- 2-s2.0-85146020154
- Other Identifier
- 991021861185604721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Medicine, Research & Experimental