Lim Han-Hyuk, Yi Haiqing, Kishimoto Takashi K, Gao Fengqin, Sun Baodong, Kishnani Priya S
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
Selecta Biosciences, Inc., Watertown, MA, United States.
Mol Genet Metab Rep. 2017 Jul 23;13:18-22. doi: 10.1016/j.ymgmr.2017.03.005. eCollection 2017 Dec.
A major obstacle to enzyme replacement therapy (ERT) with recombinant human acid-α-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. Body weight 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.
对于庞贝病患者，使用重组人酸性α-葡萄糖苷酶（rhGAA）进行酶替代疗法（ERT）的一个主要障碍是部分患者体内会产生高滴度的抗rhGAA抗体，这常常导致治疗效果丧失。为了诱导对rhGAA的持续免疫耐受，我们在GAA基因敲除小鼠12周ERT疗程的前3周，每周静脉注射携带雷帕霉素的合成疫苗颗粒（SVP-Rapa）来补充rhGAA疗法，并将其与前3周每周腹腔注射三次甲氨蝶呤（MTX）进行比较。空纳米颗粒（NP）用作SVP-Rapa的阴性对照。与用空NP或MTX治疗的小鼠相比，SVP-Rapa与rhGAA联合给药能更持久地抑制抗rhGAA抗体反应，在骨骼肌糖原清除方面具有更高的疗效，并且运动功能改善更大。在MTX治疗期间观察到体重减轻，但在SVP-Rapa治疗期间未观察到。我们的数据表明，SVP-Rapa联合给药可能是一种创新且安全的策略，可在庞贝病患者ERT期间诱导对rhGAA的持久免疫耐受，从而改善临床结局。
