Neurotensin polyplex as an efficient carrier for delivering the human GDNF gene into nigral dopamine neurons of hemiparkinsonian rats

Abstract

Recently we showed that the neurotensin polyplex is a nanoparticle carrier system that targets reporter genes in nigral dopamine neurons in vivo. Herein, we report its first practical application in experimental parkinsonism, which consisted of transfecting dopamine neurons with the gene coding for human glial cell line-derived neurotrophic factor (hGDNF). Hemiparkinsonism was induced in rats by a single dose of 6-hydroxydopamine (30 microg) into the ventrolateral part of the striatum. We showed that transfection of the hGDNF gene into the substantia nigra of rats 1 week after the neurotoxin injection produced biochemical, anatomical, and functional recovery from hemiparkinsonism. RT-PCR analysis showed mRNA expression of exogenous hGDNF in the transfected substantia nigra. Western blot analysis verified transgene expression by recognizing the flag epitope added at the C-terminus of the hGDNF polypeptide, which was found mainly in dopamine neurons by double immunofluorescence techniques. These data indicate that the neurotensin polyplex holds great promise for the neuroprotective therapy of Parkinson disease.

NT-polyplex: a new tool for therapeutic gene delivery to neuroblastoma tumors

“…The NT-polyplex is an attractive alternative because it is specific, effective, biodegradable and nontoxic. 1,3,5,8,12 The new advantage of the NT-polyplex shown in this study is the ability to effectively transfect tumoral cells after its administration through the blood stream. This feature will be of great use to target metastasis sites very small or unreachable by surgery.…”

“…5,8,11 The efficacy of the NT-polyplex is supported by the morphological and functional recovery from dopaminergic neurodegeneration in experimental hemiparkinsonism. 12 The neuroblastoma, an embryonic tumor derived from the neural crest, is the second most common solid tumor in childhood, 13 with invasion of locoregional nodes and distant metastasis in approximately 75% of cases in children older than 1 year. 14 In spite of the progress in medical and surgical treatments, long-term survival remains poor.…”

Expression patterns of the glial cell line–derived neurotrophic factor, neurturin, their cognate receptors GFRα-1, GFRα-2, and a common signal transduction element c-Ret in the human skin hair follicles

“…The antiapoptotic properties of GDNF have indeed been demonstrated in the nervous system for dopaminergic neurons of the substantia nigra in vitro. 43,44 Therefore, it is conceivable that targeting GDNF and NTN, and their cognate receptors, with appropriate agonists/antagonists deserves to be explored as a therapeutic strategy for the treatment of hair disorders related to anagen/catagen dysregulation. 45 This study provides the first evidence that GDNF, NTN, their receptors, and their common signal transduction element (c-Ret) are differentially expressed in defined compartments of the human HF and their expression is related to HF cycling.…”

Targeting delivery in Parkinson's disease

“…A targeting peptide has also been used to specifically target the neurotensin receptor of dopaminergic neurons [30]. The neurotensin peptide sequence has been added to a poly-L-lysine gene vector to deliver the GDNFencoding gene to the 6-OHDA rat model of PD [31]. Intranigral administration of the neurotensin-modified gene vector resulted in robust protection of the dying neurons, in both the substantia nigra and striatum.…”