Transduction catalysis: doxorubicin accelerates and enhances rAAV-mediated gene expression in the cortex of mouse, cat and monkey

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 vector co-infusion with doxorubicin, a clinical anti-cancer drug, markedly enhanced rAAV-mediated gene expression in the cerebral cortex across mammalian species (cat, mouse, and macaque), acting throughout the time-period examined and detectable at just three days post-transfection. This enhancement showed serotype generality, being common to rAAV serotypes 2, 8, 9 and PHP.eB tested, 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, accelerating and augmenting gene transduction at doxorubicin concentrations paralleling medical practice. HighlightsO_LIAnti-cancer drug doxorubicin doubles the rate of rAAV-mediated transgene expression C_LIO_LIDoxorubicin enhancement generalizes across rAAV serotypes and animal species C_LIO_LIThe effect is observed in both locally and retrogradely infected cortical neurons C_LIO_LIThe effective dosage is free from appreciable cytotoxicity and matches clinical settings C_LI