Near complete rescue of experimental Parkinson's disease with intravenous, non-viral GDNF gene therapy.
OBJECTIVE
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.
Zhang
Yun
Y
Department of Medicine, UCLA, Warren Hall 13-164, 900 Veteran Ave., Los Angeles, California 90024, USA.
Pardridge
William M
WM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000235:genetics* / Q000627:therapeutic use; D008081:Liposomes; D008297:Male; D020734:Parkinsonian Disorders / Q000235:genetics / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011990:Receptors, Transferrin / Q000276:immunology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000911:Antibodies, Monoclonal; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008081:Liposomes; D011990:Receptors, Transferrin; D014446:Tyrosine 3-Monooxygenase