Intravenous glial-derived neurotrophic factor gene therapy of experimental Parkinson's disease with Trojan horse liposomes and a tyrosine hydroxylase promoter.

BACKGROUND: Rats with experimental Parkinson's disease (PD) are treated with intravenous glial-derived neurotrophic factor (GDNF) plasmid DNA, non-viral gene therapy using Trojan horse liposomes (THLs) targeted with a monoclonal antibody (MAb) to the rat transferrin receptor (TfR). Expression of the transgene is confined to catecholaminergic cells by placement of the GDNF gene under the influence of the rat tyrosine hydroxylase (TH) promoter.
METHODS: A 13-kb eukaryotic expression plasmid, designated pTHpro-GDNF, is engineered in which the human prepro GDNF cDNA is driven by 8 kb of the 5'-flanking sequence of the rat TH promoter (pro), and is 3'-flanked by the bovine growth hormone transcription termination sequence. The pTHpro-GDNF plasmid DNA is encapsulated in THLs targeted with a TfRMAb, and a single intravenous injection is given to rats at 2 weeks after experimental PD is induced by intra-cerebral 6-hydroxydopamine.
RESULTS: Expression of the GDNF gene, under the influence of the TH promoter, is restricted compared to GDNF expression under the influence of the cytomegalovirus promoter. GDNF is elevated only in organs of the rat where TH gene expression is observed, including the substantia nigra, liver and adrenal gland. The single, delayed intravenous administration of the GDNF gene therapy causes a lasting reduction in apormorphine-induced rotation, which is correlated with a 19-fold increase in striatal TH enzyme activity. Both dose-response and time-responses are observed.
CONCLUSIONS: Sustained therapeutic effects are achieved in experimental PD with a delayed single intravenous dosing of GDNF plasmid DNA gene therapy, using receptor-targeted THLs and a region-specific promoter. Copyright (c) 2007 John Wiley & Sons, Ltd.