Titer and Product Affect the Distribution of Gene Expression After Intraputaminal Convection-enhanced Delivery

Overview

Journal Stereotact Funct Neurosurg

Publisher Karger

Specialty Neurosurgery

Date 2014 Jun 20

PMID 24943657

Citations 13

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

Affiliations

Soon will be listed here.

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.

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-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.

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