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

Taha Azad, Reza Rezaei, Ragunath Singaravelu, Adrian Pelin, Stephen Boulton, Julia Petryk, Kemal Alper Onsu, Nikolas T. Martin, Victoria Hoskin, Mina Ghahremani, Marie Marotel, Ricardo Marius, Xiaohong He, Mathieu J. F. Crupi, Huy-Dung Hoang, Abolfazl Nik-Akhtar, Mahsa Ahmadi, Nika Kooshki Zamani, Ashkan Golshani, Tommy Alain, Peter Greer, Michele Ardolino, Bryan C. Dickinson, Lee-Hwa Tai, Carolina S. Ilkow and John C. Bell ()
Additional contact information
Taha Azad: Ottawa Hospital Research Institute
Reza Rezaei: Ottawa Hospital Research Institute
Ragunath Singaravelu: Ottawa Hospital Research Institute
Adrian Pelin: University of California San Francisco
Stephen Boulton: Ottawa Hospital Research Institute
Julia Petryk: Ottawa Hospital Research Institute
Kemal Alper Onsu: Ottawa Hospital Research Institute
Nikolas T. Martin: Ottawa Hospital Research Institute
Victoria Hoskin: Ottawa Hospital Research Institute
Mina Ghahremani: University of Ottawa
Marie Marotel: Ottawa Hospital Research Institute
Ricardo Marius: Ottawa Hospital Research Institute
Xiaohong He: Ottawa Hospital Research Institute
Mathieu J. F. Crupi: Ottawa Hospital Research Institute
Huy-Dung Hoang: University of Ottawa
Abolfazl Nik-Akhtar: University of Ottawa
Mahsa Ahmadi: Alzahra University
Nika Kooshki Zamani: College of Science, University of Tehran
Ashkan Golshani: Carleton University
Tommy Alain: University of Ottawa
Peter Greer: Queens University
Michele Ardolino: Ottawa Hospital Research Institute
Bryan C. Dickinson: The University of Chicago
Lee-Hwa Tai: Centre de Recherche du CHUS
Carolina S. Ilkow: Ottawa Hospital Research Institute
John C. Bell: Ottawa Hospital Research Institute

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38651-x

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