Comparison of AAV Serotypes for Gene Delivery to Dopaminergic Neurons in the Substantia Nigra

Abstract

Targeted viral vector-mediated gene transfer to specific population of neurons in the central nervous system (CNS) is a relatively novel, but fast developing approach to study gene function in a number of neurodegenerative diseases (reviewed in Korecka, Verhaagen, & Hol, 2007; Manfredsson & Mandel, 2010). Moreover, several early phase clinical trials based on viral vector-mediated therapeutic gene transfer have been completed or are underway for neurological disorders (Kaplitt et al., 2007; reviewed in Korecka et al., 2007; Marks, Jr. et al., 2010; Muramatsu et al., 2010; Tuszynski et al., 2005). Gene therapy is especially attractive for diseases where neuronal degeneration is largely restricted to a single neuronal population in a specific anatomical area. Parkinson disease (PD) is a neurodegenerative disease mainly characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the Substantia Nigra (SN) (Dauer & Przedborski, 2003). It would be desirable to direct transgene expression to the dopaminergic neurons in animal models for neurodegenerative diseases, allowing for a range of investigations into the function of that gene in normal, adult DAergic neurons or following neurotoxic insult. Lentiviral vectors (LV) and adeno-associated viral vectors (AAV) are increasingly regarded as the two most useful gene therapy vectors for the CNS. Both vectors have been successfully used to express a foreign gene in a variety of brain regions and neuronal cell types (Lim, Airavaara, & Harvey, 2010; Manfredsson & Mandel, 2010; Papale, Cerovic, & Brambilla, 2009; Schneider, Zufferey, & Aebischer, 2008). LV vectors have been shown to direct long-lasting expression of a number of transgenes in the brain (Lundberg et al., 2008) including in neurons in the rat SN (Deglon et al., 2000). AAV vectors are considered to be the most appealing vectors for transgene expression in the CNS, due to their efficient neuronal transduction, their capacity to direct long-term transgene expression and their safety profile (Kaplitt et al., 2007; Mandel et al., 2006; McCown, 2005). The early AAV vectors were based on AAV serotype 2 (Kaplitt et al., 1994; Peel & Klein, 2000), but