Autosomal recessive mutations in PINK1 are a rare cause of young-onset Parkinson disease.

In vivo recombinant adeno-associated viral vector (rAAV)-mediated transduction of various tissues including brain has been characterized by slow onset and gradual increase in gene expression before reaching stable long-term protein levels. The early time course of transgene expression has not been quantified using newly available rAAV capsid serotypes. In this experiment, the onset of expression of green fluorescent protein (GFP) after intrastriatal injection of rAAV2-based pseudotyped vectors (rAAV1, rAAV5, and rAAV8 capsids) was quantified. Native GFP fluorescence displayed a delayed onset of expression of at least 7 days for all the pseudotyped rAAV vectors. However, GFP immunohistochemical staining revealed significant transgene expression by 4 days after transduction for all serotypes and stable GFP(+) neuronal populations mediated by all serotypes within 14 days post transduction at the latest. rAAV2/1 and rAAV2/2 displayed no time-dependent increase of GFP(+) striatal neurons; reaching maximal striatal cell GFP(+) counts at 4 days after injection. All serotypes displayed peak transgene expression by 4 weeks post injection where native GFP(+) neurons were equal to immunostained striatal GFP(+) neurons. The inflammatory response to these rAAV vectors was present up to 4 weeks after transduction but was not apparent 9 months post injection. Thus, rAAV-mediated transgene expression begins earlier than previously thought.

Recombinant adeno-associated virus (rAAV) is derived from a small human parvovirus with an excellent safety profile. In addition, this viral vector efficiently transduces and supports long-term transgene expression in the nervous system. These properties make rAAV a reasonable candidate vector for treating neurological disorders. Indeed, rAAV is currently being used in five early stage clinical trials for various neurodegenerative disorders. Therefore, we will review the currently available preclinical data using rAAV in animal models of central nervous system (CNS) disorders. Moreover, potential caveats for rAAV-based gene therapy in the CNS are also presented.