Adenosine deaminase (ADA)-deficient mice and healthy rhesus monkeys were studied to determine the impact of age at treatment, vector dosage, dosing schedule, repeat administration, biodistribution, and immunogenicity after systemic delivery of lentiviral vectors (LVs). In Ada -/- mice, neonatal treatment resulted in broad vector marking across all tissues analyzed, whereas adult treatment resulted in marking restricted to the liver, spleen, and bone marrow. Intravenous administration to infant rhesus monkeys also resulted in dose-dependent marking in the liver, spleen, and bone marrow. Using an ELISA to monitor anti-vector antibody development, Ada -/- neonatal mice did not produce an antibody response, whereas Ada -/- adult mice produced a strong antibody response to vector administration. In mice and monkeys with repeat administration of LV, a strong anti-vector antibody response was shown in response to the second LV administration, which resulted in LV inactivation. Three separate doses administered to immune competent mice resulted in acute toxicity. Pegylation of the vesicular stomatitis virus G protein (VSV-G)-enveloped LVs showed a less robust anti-vector response but did not prevent the inactivation of the second LV administration. These studies identify important factors to consider related to age and timing of administration when implementing systemic delivery of LVs as a potential therapeutic agent.

中文翻译：

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用于恒河猴和 ADA 缺陷小鼠体内基因治疗的慢病毒载体的给药和重新给药。


研究人员对腺苷脱氨酶 (ADA) 缺陷小鼠和健康恒河猴进行了研究，以确定治疗年龄、载体剂量、给药方案、重复给药、生物分布和系统递送慢病毒载体 (LV) 后免疫原性的影响。在 Ada -/- 小鼠中，新生儿治疗导致在所有分析的组织中产生广泛的载体标记，而成年治疗导致标记仅限于肝脏、脾脏和骨髓。对幼年恒河猴进行静脉注射也会导致肝脏、脾脏和骨髓中出现剂量依赖性标记。使用 ELISA 监测抗载体抗体的产生，Ada -/- 新生小鼠没有产生抗体反应，而 Ada -/- 成年小鼠对载体施用产生强烈的抗体反应。在重复给予 LV 的小鼠和猴子中，第二次给予 LV 后显示出强烈的抗载体抗体反应，从而导致 LV 失活。对具有免疫能力的小鼠施用三种不同的剂量导致了急性毒性。水疱性口炎病毒 G 蛋白 (VSV-G) 包膜的 LV 的聚乙二醇化表现出较弱的抗载体反应，但不能阻止第二次 LV 给药的失活。这些研究确定了在实施 LV 作为潜在治疗剂的全身给药时需要考虑的与年龄和给药时间相关的重要因素。