416. Gene Therapy for Parkinsons Disease by In Vivo Plasmid Transfer of Human Hepatocyte Growth Factor in Primate Model
Authors: Akihiko Ishida, Hiromi Koike, Ryuichi Morishita
Journal: Molecular Therapy (2006)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The ultimate treatment of PD is to protect and repair dopaminergic neurons from degenerative process. As neurotrophic factors have been shown to support the survival and enhance the function of dopaminergic neurons, gene therapy using neurotrophic factors such as glial cell line-derived neurotrophic factor becames center of interests. In the present study, we focused on hepatocyte growth factor (HGF) as a novel neurotrophic and angiogenic growth factor that is a well-known potent pleiotrophic cytokine exhibiting mitogenic, motogenic, and morphogenic activities in a variety of cells. Prevention study: we have extended the preclinical exploration to primate model of PD. Seven days after stereotaxic transfection of human HGF plasmid or lacZ plasmid into the unilateral striatum, infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the right internal carotid artery of the monkey produces toxin- induced injury to the right nigro-striatal pathway. After MPTP infusion for 4 weeks, control animals exhibited stable moderate parkinsonian features. However, primates transfecterd with HGF plasmid showed normal states. PD model primates transfected with lacZ plasmid demonstrated the apomorphine and amphetamine- induced rotational asymmetry. On the other hand, transfection of human HGF plasmid resulted in a significant inhibition of abnormal rotation for 6 months. Microdialysis demonstrated that concentrations of dopamine in striatum and substantia nigra were higher level compared with PD model and lacZ plasmid transfected animals. PET imaging demonstrated remarkable and persistent increase of [11C]-L-dopa uptake and CFT binding in HGF plasmid injected striatum, while [11C]-raclopride did not change at the HGF plasmid terated site. Overall, the present study demonstrated that over-expression of human HGF prevented neuronal death in PDmodel. Repair study: Primate models which infused MPTP into the right internal carotid artery ,exhibited stable moderate parkinsonian features. PD primates were stereotaxic transfection of human HGF plasmid or lacZ plasmid was performed into the unilateral striatum. Primates transfecterd with HGF plasmid into striatum showed to improved normal states gradually. PD model primates transfected with lacZ plasmid demonstrated the apomorphine and amphetamine- induced rotational asymmetry. On the other hand, transfection of human HGF plasmid resulted in a almost inhibition of abnormal rotation for over 6 months. Doparminergic neurons of PD model primates transfected with human HGF plasmid into striatum were repaired significantly as assessed by immunohistchemistry. The present study demonstrated that over-expression of human HGF repaired neuronal degeneration and improved of symptoms in PD model. These two studies results indicate that HGF gene therapy may represent a promising candidate treatment for PD.