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Optimization of Dexamethasone Administration for Maintaining Global Transduction Efficacy of Adeno-Associated Virus 9.

Human Gene Therapy 2019 January 32
Glucocorticoids have been commonly used in clinic due to anti-inflammatory and immunosuppressive effects and they have been proposed to be used to prevent liver toxicity when systemic administration of adeno-associated virus (AAV) vectors is needed in patients with central nervous system (CNS) diseases and muscular disorders. Glucocorticoids also enable modulation of vascular permeability. In this study we first investigated the impact of dexamethasone on AAV vascular permeability after systemic injection. When a low-dose of AAV9 was injected into the mice treated with dexamethasone, the global transduction and vector bio-distribution were not significantly different in most of the tissues other than the liver and the heart when compared to the control mice. When AAV9 vectors were used at a high dose, both the transgene expression and the AAV vector genome copy number were significantly decreased in the majority of murine tissues. However, no effect on the global transduction was observed when dexamethasone was administered 2-hours after AAV vector injection. The study on the kinetics of AAV virus clearance demonstrated that dexamethasone slowed down the clearance of AAV9 in blood after systemic application. The mechanism study showed that dexamethasone inhibited the enhancement of AAV9 vascular permeability mediated by the serum proteins. The findings indicate that dexamethasone is able to inhibit the vascular permeability of AAV and compromise the therapeutic effect after systemic administration of AAV vector. In conclusion, this study provides valuable information to design future clinical studies when glucocorticoids are needed to be compatible with the systemic administration of AAV vectors in patients with CNS and muscular diseases.

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