Gene therapy for Parkinson’s disease: AAV5-mediated delivery of glial cell line-derived neurotrophic factor (GDNF)

Abstract

Parkinson’s disease (PD) is characterized by neurodegeneration of the dopaminergic neurons. Glial cell line-derived neurotrophic factor (GDNF) has been identifi ed as possible therapeutic molecule for the treatment of neurodegenerative diseases in several different animal models. Delivery of the GDNF has been proven to be very effi cient using recombinant AAV vectors. AAV2 has been widely used for the delivery of transgenes to the brain and has even led to a clinical trial for the treatment of PD. A serotype that is known for highly effective delivery of its transgene to the brain is AAV serotype 5. At uniQure, we have developed a baculoviral-based triple infection method of SF9 insect cells that is scalable for GMP use. Using this method two AAV5 stocks encoding GDNF or GFP under control of the CAG promoter were generated and used in the current study. Biological activity of the vector was demonstrated in vitro using conditioned medium from transduced cells. In vivo analysis of the vector was performed in healthy rats following slow infusion into the brains. Recombinant AAV-mediated GDNF was detected in brain homogenates and on tissue sections. When the vector was infused in a 6-OHDA rat model, the GDNF was able to almost completely rescue the neurons in the substantia nigra. These results indicate that our viral vector can be used in an in vivo setting and can be tested in neurodegenerative disease models and further developed for possible clinical testing.