RUI JORGE GONÇALVES PEREIRA NOBRE
SILENCING MACHADO-JOSEPH DISEASE THROUGH THE SYSTEMIC ROUTE
Spinocerebellar ataxia (SCA)
Our group has recently showed that allele-specific silencing of ataxin-3 significantly decreased the severity of the neuropathological abnormalities in a rat model of Machado-Joseph disease (MJD) upon intracranial injection of lentiviral vectors (Alves et al., 2008a). Although intracranial injection is a safe procedure there is a need for a less invasive system. The aim of this project is to develop a system that will allow delivery of siRNA-based treatments to the brain by a vascular route. AAV9 vectors will be engineered to transduce neurons of the adult mouse. Silencing sequences, previously shown to efficiently abrogate MJD, will be cloned into AAV9 and its efficacy evaluated in animal models (Alves et al., 2008b). It is expected that this project will enable the development of a new gene delivery system for the treatment of MJD and constitute a proof of principle for systemic gene therapy of a wide range of neurodegenerative diseases.