Physical Sciences Division
Published May 26, 2023 | Version v1
Journal article Open

Synthetic virology approaches to improve the safety and efficacy of oncolytic virus therapies

Creators

  • 1. Ottawa Hospital Research Institute
  • 2. University of California, San Francisco
  • 3. University of Ottawa
  • 4. Alzahra University
  • 5. University of Tehran
  • 6. Carleton University
  • 7. University of Chicago

Description

The large coding potential of vaccinia virus (VV) vectors is a defining feature. However, limited regulatory switches are available to control viral replication as well as timing and dosing of transgene expression in order to facilitate safe and efficacious payload delivery. Herein, we adapt drug-controlled gene switches to enable control of virally encoded transgene expression, including systems controlled by the FDA-approved rapamycin and doxycycline. Using ribosome profiling to characterize viral promoter strength, we rationally design fusions of the operator element of different drug-inducible systems with VV promoters to produce synthetic promoters yielding robust inducible expression with undetectable baseline levels. We also generate chimeric synthetic promoters facilitating additional regulatory layers for VV-encoded synthetic transgene networks. The switches are applied to enable inducible expression of fusogenic proteins, dose-controlled delivery of toxic cytokines, and chemical regulation of VV replication. This toolbox enables the precise modulation of transgene circuitry in VV-vectored oncolytic virus design.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

The authors declare that all data supporting the conclusions of this study are presented within the paper and the supplementary information files and are available from the authors. Schematic pictures for in vivo experiments were created with BioRender.com (Figs. 1i, 2h, 3g, 5g, and 6f). Source data are provided with this paper.

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Additional details

Identifiers

DOI
10.1038/s41467-023-38651-x
Other
oai:uchicago.tind.io:6222

Funding

CIHR
CCSRI
BioCanRx
Prostate Cancer Canada
Terry Fox Research Institute
CanPRIME
Mitacs fellowship
Taggart-Parkes Fellowship
Lebovic Fellowship Funding
National Institute of General Medical Sciences
R35 GM119840

UChicago Information

Division(s)
Physical Sciences Division
Department(s)
Chemistry