1Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
2Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Hum Gene Ther. 2019 Jul;30(7):829-840. doi: 10.1089/hum.2018.233. Epub 2019 Mar 11.
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.
糖皮质激素因其抗炎和免疫抑制作用而在临床上广泛应用，有人提出，在中枢神经系统疾病和肌肉疾病患者需要全身给予腺相关病毒（AAV）载体时，可用其预防肝毒性。糖皮质激素还可调节血管通透性。本研究首先探讨了地塞米松对全身注射 AAV 后血管通透性的影响。当用低剂量 AAV9 处理的小鼠接受地塞米松治疗时，与对照小鼠相比，除肝脏和心脏外，大多数组织中的全局转导和载体生物分布没有显著差异。当使用高剂量 AAV9 载体时，大多数鼠组织中的转基因表达和 AAV 载体基因组拷贝数均显著降低。然而，当在 AAV 载体注射后 2 小时给予地塞米松时，对全局转导没有影响。对 AAV 病毒清除动力学的研究表明，地塞米松可减缓全身应用后血液中 AAV9 的清除速度。机制研究表明，地塞米松抑制了血清蛋白介导的 AAV9 血管通透性增强。研究结果表明，地塞米松能够抑制 AAV 的血管通透性，并在全身给予 AAV 载体后影响治疗效果。综上所述，本研究为设计未来的临床研究提供了有价值的信息，即在中枢神经系统和肌肉疾病患者需要与全身给予 AAV 载体兼容时，糖皮质激素的使用情况。
