Basic research on cerebellar gene therapy using lentiviral vectors.

Postmitotic neurons are resistant to gene delivery. However, lentiviral vectors allow the introduction of a foreign gene efficiently into neurons without significant toxicity to the infected cells (Sawada et al., Cerebellum 9(3):291-302, 2010). In addition, these vectors show a high tropism for neurons, and the transgenes they carry have been shown to be continuously expressed for at least a couple of years (Hirai, Cerebellum 7(3):273-8, 2008). We developed a method to express a foreign gene efficiently in cerebellar Purkinje cells in vivo (Takayama et al., Neurosci Lett 443(1):7-11, 2008; Torashima et al., Brain Res 1082(1):11-22, 2006, The Eur J Neurosci 24(2):371-80, 2006). Using our method, various experiments were carried out to study the pathophysiology of the cerebellum, including the investigation of a cerebellum-specific gene of unknown function, the generation and analysis of a mouse model of the spinocerebellar ataxia, and the rescue of an ataxic phenotype in mutant mice by introducing a defective gene or a therapeutic gene into the Purkinje cells. Here, we introduce our recent studies on expressing transgenes in the cerebellum using lentiviral vectors.