title: Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bldg. 10, Rm. 5D37, Bethesda, MD 20892-1414, USA. lonserr@ninds.nih.gov
authors.forename: R R
authors.initials: RR
authors.lastname: Lonser
authors.forename: R
authors.initials: R
authors.lastname: Schiffman
authors.forename: R A
authors.initials: RA
authors.lastname: Robison
authors.forename: J A
authors.initials: JA
authors.lastname: Butman
authors.forename: Z
authors.initials: Z
authors.lastname: Quezado
authors.forename: M L
authors.initials: ML
authors.lastname: Walker
authors.forename: P F
authors.initials: PF
authors.lastname: Morrison
authors.forename: S
authors.initials: S
authors.lastname: Walbridge
authors.forename: G J
authors.initials: GJ
authors.lastname: Murray
authors.forename: D M
authors.initials: DM
authors.lastname: Park
authors.forename: R O
authors.initials: RO
authors.lastname: Brady
authors.forename: E H
authors.initials: EH
authors.lastname: Oldfield
mesh_terms: D000818:Animals; D018481:Convection; D005776:Gaucher Disease / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000601:surgery*; D005962:Glucosylceramidase / Q000008:administration & dosage*; D006801:Humans; D007223:Infant; D008253:Macaca mulatta; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D025321:Surgery, Computer-Assisted / Q000379:methods*
chemical_list: D005962:Glucosylceramidase