title: Titer and product affect the distribution of gene expression after intraputaminal convection-enhanced delivery.
abstract: BACKGROUND
  The efficacy and safety of intracerebral gene therapy for brain disorders like Parkinson's disease depends on the appropriate distribution of gene expression.
  
  
  OBJECTIVE
  To assess whether the distribution of gene expression is affected by vector titer and protein type.
  
  
  METHODS
  Four adult macaque monkeys seronegative for adeno-associated virus 5 (AAV5) received a 30-µl inoculation of a high- or a low-titer suspension of AAV5 encoding glial cell line-derived neurotrophic factor (GDNF) or green fluorescent protein (GFP) in the right and left ventral postcommissural putamen. The inoculations were conducted using convection-enhanced delivery and intraoperative MRI (IMRI).
  
  
  RESULTS
  IMRI confirmed targeting and infusion cloud irradiation from the catheter tip into the surrounding area. A postmortem analysis 6 weeks after surgery revealed GFP and GDNF expression ipsilateral to the injection site that had a titer-dependent distribution. GFP and GDNF expression was also observed in fibers in the substantia nigra (SN) pars reticulata (pr), demonstrating anterograde transport. Few GFP-positive neurons were present in the SN pars compacta (pc), possibly by direct retrograde transport of the vector. GDNF was present in many neurons of the SNpc and SNpr.
  
  
  CONCLUSIONS
  After controlling for target and infusate volume, the intracerebral distribution of the gene product was affected by the vector titer and product biology.
authors.affiliation: Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wis., USA.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Emborg
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Hurley
authors.forename: Valerie
authors.initials: V
authors.lastname: Joers
authors.forename: Do P M
authors.initials: do PM
authors.lastname: Tromp
authors.forename: Christine R
authors.initials: CR
authors.lastname: Swanson
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ohshima-Hosoyama
authors.forename: Viktorya
authors.initials: V
authors.lastname: Bondarenko
authors.forename: Kyle
authors.initials: K
authors.lastname: Cummisford
authors.forename: Marc
authors.initials: M
authors.lastname: Sonnemans
authors.forename: Stephan
authors.initials: S
authors.lastname: Hermening
authors.forename: Bas
authors.initials: B
authors.lastname: Blits
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Alexander
mesh_terms: D000818:Animals; D018481:Convection; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D057967:Infusions, Intraventricular; D008253:Macaca mulatta; D008297:Male; D011699:Putamen / Q000601:surgery