Division of Neurosurgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
Mov Disord. 2022 Oct;37(10):2134-2139. doi: 10.1002/mds.29190. Epub 2022 Sep 11.
GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery.
This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations.
BBB permeability was achieved and restored in all patients as quantified by dynamic contrast-enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08.
Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
GBA1 突变是帕金森病（PD）最常见的遗传风险因素。溶酶体酶葡萄糖脑苷脂酶（GCase）的替代物可减缓 PD 模型中的神经退行性变，并且可能是 PD 患者有希望的疾病修饰疗法。然而，重组 GCase 通过血脑屏障（BBB）的渗透能力有限。微泡介导的磁共振引导聚焦超声（MRgFUS）可可逆地破坏 BBB 以进行药物输送。
这项开放标签的 I 期研究调查了在 4 名 GBA1 突变的 PD 患者中，每 2 周递增剂量（15 至 30 至 60IU/kg）静脉内 GCase 通过 MRgFUS 纹状体给药的安全性和可行性。
通过治疗后的动态对比增强磁共振成像定量，所有患者均实现并恢复了 BBB 通透性。没有严重的不良事件。两名患者在治疗后出现短暂的运动障碍。停药后 6 个月，盲法运动障碍协会统一帕金森病评定量表运动评分较基线下降 12%（从 26±9 降至 22±6）。氟脱氧葡萄糖正电子发射断层扫描成像中治疗纹状体的标准化摄取值比从 1.66±0.14 降至 1.27±0.08。
这项研究的结果表明，MRgFUS GCase 递送至 PD 中的安全性和可行性，并支持对此方法的进一步研究。©2022 作者。运动障碍协会由 Wiley 期刊代表国际帕金森病和运动障碍协会出版。
