First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient
First human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patient
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DOI：
10.1016/j.ymgme.2014.10.017
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发表时间：
2015-02-01
影响因子：
3.8
通讯作者：
Sly, William S.
中科院分区：
文献类型：
--
作者：
Fox, Joyce E.;Volpe, Linda;Sly, William S.
粘多糖病III型(MPS VII，Sly综合征)是一种非常罕见的溶酶体储存性疾病，由β-葡萄糖醛酸苷酶(GUS)缺乏引起，该酶是降解三种糖胺聚糖(GAG)所必需的：硫酸皮肤素、硫酸乙酰肝素和硫酸软骨素。这些GAG在溶酶体中的逐渐积累导致许多组织和器官功能障碍的增加。酶替代疗法(ERT)已经成功地用于其他MPS障碍，但还没有被批准的治疗MPS VII的方法。在这里，我们描述了人类第一次使用重组人GUS(RhGUS)治疗MPS VII，这是一种针对MPS VII的研究疗法，治疗晚期MPS VII的12岁男孩。尽管进行了气管切开、夜间持续正压和氧疗，但严重的肺限制和梗阻导致氧依赖和呼气末二氧化碳(ETCO2)水平在60-80 mm Hg范围内，最终接近呼吸衰竭(ETCO2为100 mm Hg)，需要全时呼吸机。由于没有其他治疗措施可以改善他的功能，我们实施了实验性ERT，以2 mg/kg的重组人GUS每隔2周静脉滴注一次，持续24周。安全性通过任何输液相关反应(IARs)的标准评估和遵守来评估。评估治疗前后尿GAG水平、肺功能、氧依赖、二氧化碳水平、心脏瓣膜功能、肝脾大小和生长速度。输注重组人胃肠激素耐受性良好。未观察到严重不良事件(SAE)或罐子。在开始输注rhGUS后，患者的uGAG排泄量减少了50%以上。肝和脾在第一次输液后2周内缩小，24周后恢复正常。在治疗过程中，肺功能似乎有所改善，这是基于停用呼吸机挑战后ETCO2的变化减少以及氧气需求的减少。患者恢复了吃东西的能力，体重增加，能量和活动水平增加。在24周内，每隔一周注射一次重组人胃肠激素的治疗耐受性良好，没有SAEs、IARs或过敏反应，并与客观临床测量和生活质量的可衡量改善有关。(C)2014 Elsevier Inc.保留所有权利。
Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is a very rare lysosomal storage disease caused by a deficiency of the enzyme beta-glucuronidase (GUS), which is required for the degradation of three glycosaminoglycans (GAGS): dermatan sulfate, heparan sulfate, and chondroitin sulfate. Progressive accumulation of these GAGs in lysosomes leads to increasing dysfunction in numerous tissues and organs. Enzyme replacement therapy (ERT) has been used successfully for other MPS disorders, but there is no approved treatment for MPS VII. Here we describe the first human treatment with recombinant human GUS (rhGUS), an investigational therapy for MPS VII, in a 12-year old boy with advanced stage MPS VII. Despite a tracheostomy, nocturnal continuous positive airway pressure, and oxygen therapy, significant pulmonary restriction and obstruction led to oxygen dependence and end-tidal carbon dioxide (ETCO2) levels in the 60-80 mm Hg range, eventually approaching respiratory failure (ETCO2 of 100 mm Hg) and the need for full-time ventilation. Since no additional medical measures could improve his function, we implemented experimental ERT by infusing rhGUS at 2 mg/kg over 4 h every 2 weeks for 24 weeks. Safety was evaluated by standard assessments and observance for any infusion associated reactions (IARs). Urinary GAG (uGAG) levels, pulmonary function, oxygen dependence, CO2 levels, cardiac valve function, liver and spleen size, and growth velocity were assessed to evaluate response to therapy. rhGUS infusions were well tolerated. No serious adverse events (SAEs) or JARS were observed. After initiation of rhGUS infusions, the patient's uGAG excretion decreased by more than 50%. Liver and spleen size were reduced within 2 weeks of the first infusion and reached normal size by 24 weeks. Pulmonary function appeared to improve during the course of treatment based on reduced changes in ETCO2 after off-ventilator challenges and a reduced oxygen requirement. The patient regained the ability to eat orally, gained weight, and his energy and activity levels increased. Over 24 weeks, treatment with every-other-week infusions of rhGUS was well tolerated with no SAEs, IARs, or hypersensitivity reactions and was associated with measurable improvement in objective clinical measures and quality of life. (C) 2014 Elsevier Inc. All rights reserved.