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首页> 外文期刊>Human gene therapy. Clinical development >Polyinosinic Acid Blocks Adeno-Associated Virus Macrophage Endocytosis In Vitro and Enhances Adeno-Associated Virus Liver-Directed Gene Therapy In Vivo
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Polyinosinic Acid Blocks Adeno-Associated Virus Macrophage Endocytosis In Vitro and Enhances Adeno-Associated Virus Liver-Directed Gene Therapy In Vivo

机译：聚肌苷酸可体外阻断腺相关病毒巨噬细胞的内吞作用，并增强体内腺相关病毒肝定向基因治疗。

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Adeno-associated virus serotype 8 (AAV8) has been demonstrated to be effective for liver-directed gene therapy in humans. Although hepatocytes are the main target cell for AAV8, there is a loss of the viral vector because of uptake by macrophages and Kupffer cells. Reducing this loss would increase the efficacy of viral gene therapy and allow a dose reduction. The receptor mediating this uptake has not been identified; a potential candidate seems the macrophage scavenger receptor A (SR-A) that is involved in the endocytosis of, for instance, ade-novirus. In this study we show that SR-A can mediate scAAV8 endocytosis and that blocking it with polyinosinic acid (poly[i]) reduces endocytosis significantly in vitro. Subsequently, we demonstrate that blocking this receptor improves scAAV-mediated liver-directed gene therapy in a model for inherited hyperbilirubinemia, the uridine diphospho-glucuronyl transferase lAl-deficient Gunn rat. In male rats, preadministration of poly[i] increases the efficacy of a low dose (1 x 1011 gc/kg) but not of a higher dose (3 x 1011 gc/kg) scAAV8-LP1-UT1A1. Administration of poly[i] just before the vector significantly increases the correction of serum bilirubin in female rats. In these, the effect of poly[i] is seen by both doses but is more pronounced in the females receiving the low vector, where it also results in a significant increase of bilirubin glucuronides in bile. In conclusion, this study shows that SR-A mediates the endocytosis of AAV8 in vitro and in vivo and that blocking this receptor can improve the efficacy of AAV-mediated liver-directed gene therapy.
机译：腺相关病毒血清型8（AAV8）已被证明对人类肝定向基因治疗有效。尽管肝细胞是AAV8的主要靶细胞，但由于巨噬细胞和库普弗细胞的吸收，病毒载体丢失了。减少这种损失将提高病毒基因治疗的功效，并减少剂量。尚未确定介导该摄取的受体。一个潜在的候选者似乎是巨噬细胞清道夫受体A（SR-A），它参与了例如阿德诺病毒的内吞作用。在这项研究中，我们表明SR-A可以介导scAAV8的内吞作用，并在体外用聚肌苷酸（poly [i]）阻断它可以显着降低内吞作用。随后，我们证明了在遗传性高胆红素血症模型（尿苷二磷酸-葡萄糖醛酸酰基转移酶lAl缺陷型Gunn大鼠）的模型中，阻断该受体可改善scAAV介导的肝定向基因治疗。在雄性大鼠中，预先服用poly [i]可提高低剂量（1 x 1011 gc / kg）scAAV8-LP1-UT1A1的功效，但不能提高高剂量（3 x 1011 gc / kg）的功效。在载体之前施用多聚[i]可以显着提高雌性大鼠血清胆红素的校正。在这些方法中，两种剂量都可观察到poly [i]的作用，但在接受低载体的雌性动物中更为明显，这也导致胆汁中胆红素葡萄糖醛酸苷的显着增加。总之，这项研究表明SR-A在体内和体外介导AAV8的胞吞作用，并且阻断该受体可以提高AAV介导的肝定向基因治疗的疗效。

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