Lonser R R, Schiffman R, Robison R A, Butman J A, Quezado Z, Walker M L, Morrison P F, Walbridge S, Murray G J, Park D M, Brady R O, Oldfield E H
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bldg. 10, Rm. 5D37, Bethesda, MD 20892-1414, USA.
Neurology. 2007 Jan 23;68(4):254-61. doi: 10.1212/01.wnl.0000247744.10990.e6. Epub 2006 Oct 25.
To determine if convection-enhanced delivery (CED) of glucocerebrosidase could be used to treat targeted sites of disease progression in the brain and brainstem of a patient with neuronopathic Gaucher disease while monitoring enzyme distribution using MRI.
A CED paradigm in rodents (n = 8) and primates (n = 5) that employs co-infusion of a surrogate MRI tracer (gadolinium diethylenetriamine penta-acetic acid [Gd-DTPA]) with glucocerebrosidase to permit real-time monitoring of distribution was developed. The safety and feasibility of this delivery and monitoring paradigm were evaluated in a patient with type 2 Gaucher disease.
Animal studies revealed that real-time, T1-weighted, MRI of Gd-DTPA accurately tracked enzyme distribution during CED. Targeted perfusion of clinically affected anatomic sites in a patient with neuronopathic Gaucher disease (frontal lobe and brainstem) with glucocerebrosidase was successfully performed. Real-time MRI revealed progressive and complete filling of the targeted region with enzyme and Gd-DTPA infusate. The patient tolerated the infusions without evidence of toxicity.
Convection-enhanced delivery can be used to safely perfuse large regions of the brain and brainstem with therapeutic levels of glucocerebrosidase. Co-infused imaging surrogate tracers can be used to monitor and control the distribution of therapeutic agents in vivo. Patients with neuronopathic Gaucher disease and other intrinsic CNS disorders may benefit from a similar treatment paradigm.
确定在使用磁共振成像（MRI）监测酶分布的同时，葡萄糖脑苷脂酶的对流增强递送（CED）是否可用于治疗神经元型戈谢病患者大脑和脑干中疾病进展的靶向部位。
开发了一种在啮齿动物（n = 8）和灵长类动物（n = 5）中使用替代MRI示踪剂（钆二乙烯三胺五乙酸[Gd-DTPA]）与葡萄糖脑苷脂酶共同输注以实现分布实时监测的CED模式。在一名2型戈谢病患者中评估了这种递送和监测模式的安全性和可行性。
动物研究表明，在CED期间，Gd-DTPA的实时T1加权MRI准确跟踪了酶的分布。成功地对一名神经元型戈谢病患者（额叶和脑干）的临床受累解剖部位进行了葡萄糖脑苷脂酶的靶向灌注。实时MRI显示靶向区域逐渐并完全被酶和Gd-DTPA输注液充满。患者耐受输注且无毒性证据。
对流增强递送可用于将治疗水平的葡萄糖脑苷脂酶安全地灌注到大脑和脑干的大片区域。共同输注的成像替代示踪剂可用于监测和控制体内治疗剂的分布。神经元型戈谢病和其他中枢神经系统内在疾病的患者可能受益于类似的治疗模式。
