Neuroprotection in a rat Parkinson model by GDNF gene therapy using EIAV vector

Abstract

Vectors based on lentiviruses are opening up new approaches for the treatment of neurodegenerative diseases. Currently, the equine infectious anaemia virus (EIAV) vector is one of the most attractive gene delivery systems with respect to neuronal tropism. The aim was to validate EIAV-lentiviral vectors as a gene delivery system for neurotrophic factor genes in an animal model of Parkinson's disease. EIAV carrying the glial cell line-derived neurotrophic factor (GDNF) gene was unilaterally injected into rat striatum and above the substantia nigra (SN). One week later, the rats received a 6-OHDA lesion into the ipsilateral striatum. GDNF delivery led to extensive expression of GDNF protein within the striatum. In addition, near complete protection against dopaminergic cell death was observed in the GDNF-treated group.

Actions of GDNF on Midbrain Dopaminergic Neurons: The Signaling Pathway

“…Additionally, studies have demonstrated that GDNF can selectively protect DA-ergic neurons against the neurotoxic effects exerted by methylamphetamine (Cass, 1996). Thus far, GDNF, as a potential therapeutic agent for PD, has been studied extensively (Azzouz et al, 2004;Eslamboli et al, 2005). Further research has demonstrated that GDNF can modulate neuronal excitability and transmitter release (Wang et al, 2003;Kobori et al, 2004).…”

Gene therapy in Parkinson?s disease

“…A LV-Tet-off system is being tested in monkeys (Kordower 2003). An equine infectious anemia virus vector apathogenic to humans has recently been tested successfully in a rodent PD model (Azzouz et al 2004). …”

Safety and Function of a New Clinical Intracerebral Microinjection Instrument for Stem Cells and Therapeutics Examined in the Göttingen Minipig

“…Basal ganglia dysfunction may, accordingly, be partially corrected by subthalamic or pallidal implantation of deep brain stimulation electrodes [3] , while striatal dopamine deficiency may be rectified by implantation of embryonic dopaminergic cells [1,2,4,5] . Moreover, several preclinical studies have shown that gene therapy involving the injection of viral vectors encoding for enzymes [6,7] , antiapoptotic [8,9] or trophic factors [10][11][12][13][14] may become viable approaches in the treatment of Parkinson disease. Although implantation of stem cells and viral vectors has shown promise in animal models, the clinical experiences have been less encouraging [4,11,15,16] .…”