Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
Genet Med. 2016 Jan;18(1):73-81. doi: 10.1038/gim.2015.36. Epub 2015 Apr 2.
Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid.
Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly.
No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months.
These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81.
约三分之二患有黏多糖贮积症 II 型的患者存在进行性认知障碍。静脉内（iv）酶替代疗法不能影响认知障碍，因为重组艾杜糖-2-硫酸酯酶（伊杜硫酸酯酶）在治疗浓度下不能穿透血脑屏障。我们研究了鞘内给药（伊杜硫酸酯酶-IT）用伊杜硫酸酯酶配方的安全性，通过鞘内药物输送装置（IDDD）。次要终点是脑脊液中糖胺聚糖浓度的变化。
16 名认知障碍的男性黏多糖贮积症 II 型患者，之前接受每周静脉内 0.5mg/kg 伊杜硫酸酯酶治疗≥6 个月，入组。患者随机分为无治疗组或每月接受 10mg、30mg 或 1mg 伊杜硫酸酯酶-IT，持续 6 个月（每组 4 名患者），同时每周继续静脉内伊杜硫酸酯酶治疗。
未观察到与伊杜硫酸酯酶-IT 相关的严重不良事件。12 名患者中有 6 名需要进行 IDDD 的手术修订/移除。通过腰椎穿刺共给予 12 个总剂量。10mg 和 30mg 组在 6 个月后，平均脑脊液糖胺聚糖浓度降低了约 90%，1mg 组降低了约 80%。
这些初步数据支持进一步开发研究性伊杜硫酸酯酶-IT 在具有严重表型的 MPS II 患者中的应用，这些患者仅进展到轻度至中度认知障碍水平。遗传医学 18 卷 1 期，73-81 页。
