Highly Efficient Retrograde Gene Transfer for Genetic Treatment of Neurological Diseases

Abstract

Gene transfer vectors derived from neurotropic viruses provide a powerful tool for gene therapy of a variety of neurological diseases. The lentiviral vector system permits the efficient transfer of genes into non-dividing cells in the central nervous system and sustains long-term expression of the genes (Naldini et al., 1996; Reiser et al., 1996; Mochizuki et al., 1998; Mitrophanous et al., 1999). This vector system has been used for gene therapy trials in animal models for neurological diseases (for reviews, see Azzouz et al., 2004a; Wong et al., 2006; Lundberg et al., 2008). Axonal transport in the retrograde direction, as observed in the case of some viral vectors, has a considerable advantage for transferring genes into neuronal cell bodies situated in regions remote from the injection sites of the vectors (see Fig. 1). These viral vectors, when injected into the striatum, deliver the genes through retrograde transport into nigrostriatal dopamine neurons that are the major target for gene therapy of Parkinson’s disease (Zheng et al., 2005; Barkats et al., 2006). Intramuscular injection of the vectors also delivers retrogradely the genes into motor neurons that are the target for gene therapy of motor neuron diseases (Baumgartner & Shine, 1998; Perrelet et al., 2000; Mazarakis et al., 2001; Sakamoto et al., 2003; Azzouz et al., 2004b). To enhance the gene transfer of a human immunodeficiency virus type-1 (HIV-1)-based vector via retrograde transport, we have previously generated the HIV-1 vector pseudotyped with a selective variant of rabies virus glycoprotein (RV-G) (Kato et al., 2007). Injection of this RV-G-pseudotyped vector into the mouse striatum yields an increase in gene transfer into neuronal populations in the cerebral cortex, thalamus, and ventral midbrain, each of which innervates the striatum. Injection of the RV-G pseudotype into the monkey striatum (caudate and putamen) results in increased gene transfer into the nigrostriatal dopamine neurons. The RV-G pseudotyping of the HIV-1 vector enhances the efficiency of gene transfer through retrograde axonal transport in the rodent and nonhuman primate brains. However, because large-scale application of gene therapy trials requires