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Titer and product affect the distribution of gene expression after intraputaminal convection-enhanced delivery.
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Stereotact Funct Neurosurg 2014 ; 92(3):182-94
Authors: Marina E Emborg, Samuel A Hurley, Valerie Joers, Do P M Tromp, Christine R Swanson, Sachiko Ohshima-Hosoyama, Viktorya Bondarenko, Kyle Cummisford, Marc Sonnemans, Stephan Hermening, Bas Blits, Andrew L Alexander
Background: The efficacy and safety of intracerebral gene therapy for brain disorders like Parkinson's disease depends on the appropriate distribution of gene expression. Objectives: 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-Ķl 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. © 2014 S. Karger AG, Basel.
PMID: 24943657 [PubMed - as supplied by publisher]