Yun Zhang1, William M Pardridge. 1. Department of Medicine, UCLA, Warren Hall 13-164, 900 Veteran Ave., Los Angeles, California 90024, USA.
Abstract
PURPOSE: Rats with experimental Parkinson's disease (PD) are treated with intravenous glial-derived neurotrophic factor (GDNF) plasmid DNA and non-viral gene therapy using Trojan horse liposomes (THLs) targeted with a monoclonal antibody (MAb) to the rat transferrin receptor (TfR). The GDNF transgene expression is under the influence of the rat tyrosine hydroxylase (TH) promoter. METHODS: The GDNF expression plasmid is designated pTHproGDNF. Rats were treated with 3 weekly injections of THLs starting 1 week after the intra-cerebral injection of 6-hydroxydopamine. The dose of the pTHproGDNF was 10 mICROg/rat/weekly injection. Rats were tested with three assays of neurobehavior, and terminal striatal TH enzyme activity was measured at 6 weeks following toxin administration, which is 3 weeks following the last administration of THLs. RESULTS: Apomorphine-induced contralateral rotation was reduced 87% by THL gene therapy; amphetamine-induced ipsilateral rotation was reduced 90% by THL gene therapy; whisker-induced forelimb placement abnormalities were reduced 77% with THL gene therapy. The improvement in neurobehavior correlated with a lasting 77% increase in striatal TH enzyme activity, relative to saline treated rats. CONCLUSIONS: Near complete abrogation of the neurotoxin effects are achieved with multiple intravenous dosing of GDNF plasmid DNA gene therapy, using receptor-targeted THLs, and a region-specific promoter.
PURPOSE:Rats with experimental Parkinson's disease (PD) are treated with intravenous glial-derived neurotrophic factor (GDNF) plasmid DNA and non-viral gene therapy using Trojan horse liposomes (THLs) targeted with a monoclonal antibody (MAb) to the rattransferrin receptor (TfR). The GDNF transgene expression is under the influence of the rat tyrosine hydroxylase (TH) promoter. METHODS: The GDNF expression plasmid is designated pTHproGDNF. Rats were treated with 3 weekly injections of THLs starting 1 week after the intra-cerebral injection of 6-hydroxydopamine. The dose of the pTHproGDNF was 10 mICROg/rat/weekly injection. Rats were tested with three assays of neurobehavior, and terminal striatal TH enzyme activity was measured at 6 weeks following toxin administration, which is 3 weeks following the last administration of THLs. RESULTS:Apomorphine-induced contralateral rotation was reduced 87% by THL gene therapy; amphetamine-induced ipsilateral rotation was reduced 90% by THL gene therapy; whisker-induced forelimb placement abnormalities were reduced 77% with THL gene therapy. The improvement in neurobehavior correlated with a lasting 77% increase in striatal TH enzyme activity, relative to saline treated rats. CONCLUSIONS: Near complete abrogation of the neurotoxin effects are achieved with multiple intravenous dosing of GDNF plasmid DNA gene therapy, using receptor-targeted THLs, and a region-specific promoter.
Authors: Kristin K Anstrom; Timothy Schallert; Martin T Woodlee; Avery Shattuck; David C S Roberts Journal: Behav Brain Res Date: 2007-02-03 Impact factor: 3.332
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