ABSTRACT
CNS gene transfer could provide new approaches to the modelling of neurodegenerative diseases and devising potential therapies. One such disorder is Parkinson's disease (PD), in which dysfunction of several different metabolic processes has been implicated. Here we review the literature on gene transfer systems based on herpes simplex virus type 1 (HSV-1) and non-viral polyethyleneimine (PEI) and calcium phosphate nanoparticle methods. We also assess the usefulness of various CNS gene delivery methods and present some of our own data to exemplify such usefulness. Our data result from vectors stereotaxically introduced to the substantia nigra (SN) of adult rats and evaluated 1 week and/or 1 month post injection using histochemical methods to assess recombinant ss-galactosidase enzyme activity. Gene transfer using PEI or calcium phosphate-mediated transfections was observed for both methods and PEI was comparable to that of HSV-1 amplicon. Our data show that the amplicon delivery was markedly increased when packaged with a helper virus and was similar to the expression profile achieved with a full-size replication-defective HSV-1 recombinant (8117/43). We also examine whether PEI or HSV-1 amplicon-mediated gene transfer could facilitate assessment of the biological effects induced by a dominant negative FGF receptor-1 mutant to model the reduced FGF signalling thought to occur in Parkinson's disease.
Subject(s)
Calcium Phosphates/chemistry , Genetic Vectors , Herpesvirus 1, Human/genetics , Parkinson Disease/etiology , Polyethyleneimine/chemistry , Receptor Protein-Tyrosine Kinases , Receptors, Fibroblast Growth Factor , Substantia Nigra/metabolism , Animals , Animals, Newborn , Brain/metabolism , Brain/pathology , Brain/virology , Cells, Cultured , Cricetinae , Mice , NIH 3T3 Cells , Nanotechnology , Rats , Receptor Protein-Tyrosine Kinases/chemistry , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, Fibroblast Growth Factor, Type 1 , Receptors, Fibroblast Growth Factor/chemistry , Receptors, Fibroblast Growth Factor/genetics , Receptors, Fibroblast Growth Factor/metabolism , Substantia Nigra/virology , Transduction, Genetic/methodsABSTRACT
The effects of HSV-1 amplicon and polyethyleneimine (PEI)-mediated transfection of dominant negative FGF receptor-1 mutant FGFR1(TK-) into the rat brain substantia nigra (SN) were examined in vivo to model the reduced FGF signaling documented to occur in Parkinson's disease. The number of SN neurons that expressed tyrosine hydroxylase (TH) was significantly reduced following HSV-1 FGFR1(TK-) intranigral delivery and similar changes were observed after PEI-mediated FGFR1(TK-) transfections. Further, we also observed a significantly lower striatal dopamine content following the PEI transfection of FGFR1(TK-). Thus, we conclude that reduced FGF signaling in the SN of Parkinsonian patients could play a role in the impaired dopaminergic transmission associated with the degenerative disease.
