A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease
A pilot study on using rapamycin-carrying synthetic vaccine particles (SVP) in conjunction with enzyme replacement therapy to induce immune tolerance in Pompe disease
复制标题
DOI：
10.1016/j.ymgmr.2017.03.005
复制
发表时间：
2017-12-01
影响因子：
1.9
通讯作者：
Kishnani, Priya S.
中科院分区：
文献类型：
--
作者：
Lim, Han-Hyuk;Yi, Haiqing;Kishnani, Priya S.
使用重组人酸性α-葡萄糖苷酶(RhGAA)进行酶替代疗法(ERT)治疗Pompe病的一个主要障碍是在一部分患者中产生高滴度的抗rhGAA抗体，这往往导致治疗效果的丧失。为了诱导对rhGAA的持续免疫耐受，在GAA-KO小鼠12周ERT的前3周，我们在rhGAA治疗的基础上，每周静脉注射携带雷帕霉素的合成疫苗颗粒(SVP-RAPA)，并与前3周每周三次腹腔注射甲氨蝶呤(MTX)进行比较。以空纳米粒(NP)作为SVP-RAPA的阴性对照。与空白NP或MTX组相比，SVP-RAPA与rhGAA联合给药对抗rhGAA抗体反应的抑制作用更持久，对骨骼肌糖原清除的效率更高，运动功能改善更明显。在MTX治疗期间观察到体重减轻，但在SVP-Rapa治疗期间没有观察到体重减轻。我们的数据表明，联合应用SVP-RAPA可能是一种创新和安全的策略，可以在Pompe病患者ERT期间诱导对rhGAA的持久免疫耐受，从而改善临床结果。(C)2017年作者。由爱思唯尔公司出版。
A major obstacle to enzyme replacement therapy (ERT) with recombinant human acid-a-glucosidase (rhGAA) for Pompe disease is the development of high titers of anti-rhGAA antibodies in a subset of patients, which often leads to a loss of treatment efficacy. In an effort to induce sustained immune tolerance to rhGAA, we supplemented the rhGAA therapy with a weekly intravenous injection of synthetic vaccine particles carrying rapamycin (SVP-Rapa) during the first 3 weeks of a 12-week course of ERT in GAA-KO mice, and compared this with three intraperitoneal injections of methotrexate (MTX) per week for the first 3 weeks. Empty nanoparticles (NP) were used as negative control for SVP-Rapa. Co-administration of SVP-Rapa with rhGAA resulted in more durable inhibition of anti-rhGAA antibody responses, higher efficacy in glycogen clearance in skeletal muscles, and greater improvement of motor function than mice treated with empty NP or MTX. Bodyweight loss was observed during the MTX-treatment but not SVP-Rapa-treatment. Our data suggest that co-administration of SVP-Rapa may be an innovative and safe strategy to induce durable immune tolerance to rhGAA during the ERT in patients with Pompe disease, leading to improved clinical outcomes. (C) 2017 The Authors. Published by Elsevier Inc.