Preclinical evaluation of a novel AAV-GDF5 vector in a 6-OHDA model of Parkinson’s disease and evaluation of the effect of 6-OHDA on the expression of HDACs

Neurotrophic factors have shown promising results as potential disease-altering treatment methods for Parkinson’s disease (PD). However, there are many risks associated with surgically accessing such deeply located regions of the brain as the striatum or substantia nigra. Directly administered proteins will be broken down, meaning that such an intervention would have short-lived benefits. For this reason, the use of viral vectors to deliver neurotrophic factor genes has become a popular alternative, as this would allow for prolonged expression of the neurotrophic factor. In this study, we used an AAV2/5 vector to deliver GDF5 to the substantia nigra of rats, both at the same time as striatal administration of 6-OHDA and two weeks prior to 6-OHDA administration. We found that those animals which received AAV2/5-GDF5 had similar levels of TH immunopositive cell body loss in the substantia nigra and similar decreases in TH immunstaining in the striatum as those animals which had just received 6-OHDA. The 6-OHDA rodent model is commonly used in PD research. As such, it is important to understand the characteristics of this model in order to best interpret observations made when using this model. In this study we examined how 6-OHDA administration affects HDAC3, 5 and 9 expression in the rat brain. HDAC5 and HDAC9 are of particular interest to our group as our group has shown that their expression correlates with three markers of dopaminergic neurons in both the mouse and human substantia nigra. HDAC3 was also selected as an example of a different HDAC class. We found that striatal administration of 6-OHDA resulted in bilaterally increased expression of HDAC3 and 9 in the striatum, no changes were seen in HDAC3 in the midbrain, while HDAC9 was unilaterally upregulated in the midbrain. HDAC5 is known to shuttle between the nucleus and the cytoplasm of the cell. For this reason, we examined nuclear and cytop-lasmic levels of HDAC5. HDAC5 was also found to be upregulated bilaterally in the midbrain and it was observed that this increase was restricted to the nucleus