Transduction catalysis: Doxorubicin amplifies rAAV-mediated gene expression in the cortex of higher-order vertebrates

Hongliang Gong; Nini Yuan; Zhiming Shen; Cheng Tang; Stewart Shipp; Liling Qian; Yiliang Lu; Ian Max Andolina; Shenghai Zhang; Jihong Wu; Hui Yang; Wei Wang

doi:10.1016/j.isci.2021.102685

Transduction catalysis: Doxorubicin amplifies rAAV-mediated gene expression in the cortex of higher-order vertebrates

iScience. 2021 Jun 4;24(6):102685. doi: 10.1016/j.isci.2021.102685. eCollection 2021 Jun 25.

Authors

Hongliang Gong^{1

2}, Nini Yuan¹, Zhiming Shen¹, Cheng Tang^{1

2}, Stewart Shipp¹, Liling Qian¹, Yiliang Lu¹, Ian Max Andolina¹, Shenghai Zhang³, Jihong Wu³, Hui Yang^{1

2

4}, Wei Wang^{1

2

4}

Affiliations

¹ Institute of Neuroscience, the Center for Excellence in Brain Science and Intelligence Technology, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Chinese Academy of Sciences, Shanghai 200031, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai 200031, China.
⁴ Shanghai Center for Brain and Brain-Inspired Intelligence Technology, Shanghai 200031, China.

Abstract

Rapid and efficient gene transduction via recombinant adeno-associated viruses (rAAVs) is highly desirable across many basic and clinical research domains. Here, we report that vector co-infusion with doxorubicin, a clinical anti-cancer drug, markedly enhanced rAAV-mediated transgene expression in the cerebral cortex across mammalian species (cat, mouse, and macaque), acting throughout the time period examined and detectable at just three days after transfection. This enhancement showed serotype generality, being common to all rAAV serotypes tested (2, 8, 9, and PHP.eB) and was observed both locally and at remote locations consistent with doxorubicin undergoing retrograde axonal transport. All these effects were observed at doses matching human blood plasma levels in clinical therapy and lacked detectable cytotoxicity as assessed by cell morphology, activity, apoptosis, and behavioral testing. Altogether, this study identifies an effective means to improve the capability and scope of in vivo rAAV applications, amplifying cell transduction at doxorubicin concentrations paralleling medical practice.

Keywords: Molecular biology; Molecular neuroscience; Neuroscience.