Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector.
Transient immunosuppression permits successful repetitive intravenous administration of an adenovirus vector.
复制标题
瞬时免疫抑制允许成功地重复静脉内施用腺病毒载体。
作者：
T. Smith;B. White;J. M. Gardner;M. Kaleko;A. Mcclelland
腺病毒载体的体内给药经常引起中和抗体反应，从而消除或显著降低后续治疗的效果。以腺病毒为基础的基因治疗在慢性疾病治疗中的应用需要克服重复递送这一重大障碍的方法。我们已经评估了初始媒介剂量和第二次媒介注射效果之间的关系。C57BL/6小鼠静脉注射高达10(7)p.f.u。当注射2×10(8)p.f.u时，LacZ腺病毒载体Av1lacZ4表达了显著水平的人凝血因子IX。因子IX载体Av1H9F，5周后。初始剂量为10(8)p.f.u。Av1lacZ4在第二次给药后由于产生中和抗体而完全阻止了因子IX的表达。然而，在首次暴露于10(8)p.f.u时，用脱氧精灵(DSG)或环磷酰胺进行一过性免疫抑制。Av1lacZ4的产生阻止了抗腺病毒中和抗体的形成，并允许有效的第二次注射因子IX载体。此外，环磷酰胺的短暂免疫抑制伴随着因子IX载体的传递，使得能够有效地管理编码人因子VIII的第三个载体。这种方法，加上延长腺病毒载体表达的持续时间的策略，应该允许对腺病毒载体的长期治疗。
The in vivo administration of adenovirus vectors frequently elicits a neutralizing antibody response which eliminates or substantially reduces the efficacy of subsequent treatments. Methods to overcome this significant barrier to repeat delivery will be required for the application of adenovirus-based gene therapy in the treatment of chronic disease. We have evaluated the relationship between the initial vector dose and the effectiveness of a second vector administration. C57BL/6 mice injected intravenously with up to 10(7) p.f.u. of a lacZ adenovirus vector, Av1lacZ4, expressed significant levels of human factor IX when injected with 2 x 10(8) p.f.u. of the factor IX vector, Av1H9F, 5 weeks later. An initial dose of 10(8) p.f.u. of Av1lacZ4 completely prevented expression of factor IX following the second administration due to the generation of neutralizing antibody. However, transient immunosuppression with deoxyspergualin (DSG) or cyclophosphamide at the time of initial exposure to 10(8) p.f.u. of Av1lacZ4 prevented the formation of anti-adenovirus neutralizing antibody and permitted an effective second administration of a factor IX vector. Furthermore, transient immunosuppression with cyclophosphamide concomitant with delivery of the factor IX vector enabled an effective administration of a third vector encoding human factor VIII. This approach, together with strategies to prolong the persistence of adenoviral vector expression, should permit long-term therapy with adenovirus-based vectors.