Peng Jeffrey, Dalton Jill, Butt Mark, Tracy Kristin, Kennedy Derek, Haroldsen Peter, Cahayag Rhea, Zoog Stephen, O'Neill Charles A, Tsuruda Laurie S
BioMarin Pharmaceutical Inc., Novato, California (J.P., K.T., P.H., R.C., S.Z., C.A.O., L.S.T.); MPI Research, Mattawan, Michigan (J.D.); Tox Path Specialists, LLC, Frederick, Maryland (M.B.); UltraGenyx Pharmaceutical Inc., Novato, California (D.K.).
BioMarin Pharmaceutical Inc., Novato, California (J.P., K.T., P.H., R.C., S.Z., C.A.O., L.S.T.); MPI Research, Mattawan, Michigan (J.D.); Tox Path Specialists, LLC, Frederick, Maryland (M.B.); UltraGenyx Pharmaceutical Inc., Novato, California (D.K.)
J Pharmacol Exp Ther. 2017 Feb;360(2):313-323. doi: 10.1124/jpet.116.235952. Epub 2016 Nov 16.
Pompe disease is a rare neuromuscular disorder caused by an acid α-glucosidase (GAA) deficiency resulting in glycogen accumulation in muscle, leading to myopathy and respiratory weakness. Reveglucosidase alfa (BMN 701) is an insulin-like growth factor 2-tagged recombinant human acid GAA (rhGAA) that enhances rhGAA cellular uptake via a glycosylation-independent insulin-like growth factor 2 binding region of the cation-independent mannose-6-phosphate receptor (CI-MPR). The studies presented here evaluated the effects of Reveglucosidase alfa treatment on glycogen clearance in muscle relative to rhGAA, as well as changes in respiratory function and glycogen clearance in respiratory-related tissue in a Pompe mouse model (GAA/J). In a comparison of glycogen clearance in muscle with Reveglucosidase alfa and rhGAA, Reveglucosidase alfa was more effective than rhGAA with 2.8-4.7 lower EC values, probably owing to increased cellular uptake. The effect of weekly intravenous administration of Reveglucosidase alfa on respiratory function was monitored in Pompe and wild-type mice using whole body plethysmography. Over 12 weeks of 20-mg/kg Reveglucosidase alfa treatment in Pompe mice, peak inspiratory flow (PIF) and peak expiratory flow (PEF) stabilized with no compensation in respiratory rate and inspiratory time during hypercapnic and recovery conditions compared with vehicle-treated Pompe mice. Dose-related decreases in glycogen levels in both ambulatory and respiratory muscles generally correlated to changes in respiratory function. Improvement of murine PIF and PEF were similar in magnitude to increases in maximal inspiratory and expiratory pressure observed clinically in late onset Pompe patients treated with Reveglucosidase alfa (Byrne et al., manuscript in preparation).
庞贝病是一种罕见的神经肌肉疾病，由酸性α-葡萄糖苷酶（GAA）缺乏引起，导致糖原在肌肉中积累，进而引发肌病和呼吸肌无力。瑞弗葡糖苷酶α（BMN 701）是一种胰岛素样生长因子2标记的重组人酸性GAA（rhGAA），它通过阳离子非依赖性甘露糖-6-磷酸受体（CI-MPR）的非糖基化依赖性胰岛素样生长因子2结合区域增强rhGAA的细胞摄取。本文介绍的研究评估了瑞弗葡糖苷酶α治疗相对于rhGAA对肌肉中糖原清除的影响，以及在庞贝病小鼠模型（GAA/J）中呼吸功能和呼吸相关组织中糖原清除的变化。在比较瑞弗葡糖苷酶α和rhGAA对肌肉糖原清除的效果时，瑞弗葡糖苷酶α比rhGAA更有效，其半数有效浓度（EC）值低2.8 - 4.7，这可能是由于细胞摄取增加所致。使用全身体积描记法监测了庞贝病小鼠和野生型小鼠每周静脉注射瑞弗葡糖苷酶α对呼吸功能的影响。在庞贝病小鼠中，用20 mg/kg瑞弗葡糖苷酶α治疗12周后，与载体处理的庞贝病小鼠相比，在高碳酸血症和恢复条件下，吸气峰流量（PIF）和呼气峰流量（PEF）稳定，呼吸频率和吸气时间无代偿变化。活动肌肉和呼吸肌肉中糖原水平的剂量相关下降通常与呼吸功能的变化相关。瑞弗葡糖苷酶α治疗后小鼠PIF和PEF的改善幅度与在接受瑞弗葡糖苷酶α治疗的晚发型庞贝病患者中观察到的最大吸气和呼气压力增加幅度相似（Byrne等人，正在准备的手稿）。
