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

Glucocorticoids have been commonly used in clinic for their anti-inflammatory and immunosuppressive effects, and it has been proposed that they be used to prevent liver toxicity when systemic administration of adeno-associated virus (AAV) vectors is needed in patients with central nervous system diseases and muscular disorders. Glucocorticoids also enable modulation of vascular permeability. First, this study investigated the impact of dexamethasone on AAV vascular permeability after systemic injection. When a low dose of AAV9 was injected into mice treated with dexamethasone, global transduction and vector biodistribution were not significantly different in most tissues, other than the liver and the heart, when compared to 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 global transduction was observed when dexamethasone was administered 2 h after AAV vector injection. The study on the kinetics of AAV virus clearance demonstrated that dexamethasone slowed down the clearance of AAV9 in the blood after systemic application. The mechanism study showed that dexamethasone inhibited the enhancement of AAV9 vascular permeability mediated by 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 for the design of future clinical studies when glucocorticoids are needed to be compatible with the systemic administration of AAV vectors in patients with central nervous system and muscular diseases.