UCLA

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. 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 μg/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. 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. 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.