Prevention of onset of Parkinson’s disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson’s disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SNi). As neurotrophic factors support the survival and enhance the function of dopaminergic neurons, gene therapy using neurotrophic factors has become the center of interest. Thus, we focused on hepatocyte growth factor (HGF) as a neurotrophic and angiogenic growth factor. At 7 days before injection of 6-hydroxydopamine into the SNi, stereotaxic transfection of human HGF or lacZ plasmid was performed into the unilateral striatum of rats. Expression of human HGF in the injected sites could be detected in rats transfected with HGF plasmid DNA, using immunohistochemical staining. Consistently, human immunoreactive HGF protein could be detected at least up to 12 days after transfection. Interestingly, PD rats transfected with lacZ demonstrated amphetamine-induced rotational asymmetry. However, transfection of HGF plasmid DNA resulted in significant inhibition of abnormal rotation up to 24 weeks in a dose-dependent manner. Over 90% of dopaminergic neurons were lost in PD rats transfected with lacZ, whereas over 70% survived in rats transfected with HGF, as assessed by immunohistochemical staining. Overall, the present study demonstrated that overexpression of HGF prevented neuronal death in a PD rat model, providing a potential novel therapy for PD.

Injection of HGF Plasmid cDNA to Prevent Manifestation of Parkinson Disease: A Preclinical Study using a Primate Model

“…Aiming toward human gene therapy, we employed a hemi-parkinson primate to test the feasibility of gene therapy. Consistent with a rat study [31], transfection of human HGF plasmid DNA by direct injection into the primate putamen using a stereotaxic technique resulted in the detection of immunoreactive human HGF protein, while the untransfected contralateral side was not stained (Fig. 1a).…”

“…This study demonstrated the therapeutic potential of HGF in a hemi-PD primate model, and we also obtained similar results in a rat PD model [31]. While further studies after the onset of PD are necessary for progressing toward human therapy, HGF might have therapeutic value to treat PD.…”

The Procognitive and Synaptogenic Effects of Angiotensin IV–Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System

“…HGF is a potent neurotrophic factor in many brain regions (Ebens et al, 1996;Kato et al, 2003), affecting a variety of neuronal cell types. Activation of the HGF/c-Met system has been shown to possess neuroprotective/neurorestorative activity related to amyotrophic lateral sclerosis (Kadoyama et al, 2007), Parkinson's disease (Koike et al, 2006;Lan et al, 2008), spinal cord trauma (Kitamura et al, 2011), and multiple sclerosis (Bai et al, 2012). Moreover, activation of the HGF/ c-Met system improves cognition (Akimoto et al, 2004)-an whereas Hinge had no effect on basal frequencies.…”

Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine: implications for reparative therapy in Parkinson’s disease

“…In particular, levels of VEGF, HGF and KGF were markedly reduced compared to control treatments, suggesting that their uptake by mdNSCs may underlie the protective effects. It has been demonstrated that human NSCs migrate towards injured adult spinal cord in a HGF-dependent manner [49], and that over-expression of HGF can prevent neuronal death in a rat model of PD [50]. HGF also protects human embryonic stem cell derived-neural progenitors from hydrogen peroxide-induced apoptosis by preventing the subsequent Bcl-2 protein diminution [51].…”