This grant builds upon the research from a prior grant: Selective Inhibition of Cyclic Nucleotide Phosphodiesterase Type 7 (PDE7): A Novel and Efficacious Approach to Treating Parkinson's Disease
Promising Outcomes of Original Grant:
We are investigating a regulatory enzyme (type-7 cyclic nucleotide phosphodiesterase, PDE7) as a novel therapeutic target for the treatment of Parkinson’s disease. Our findings to date have shown that inhibitors of PDE7 are highly effective in one pre-clinical MPTP model but lack efficacy in another model. In the first model, we have found that PDE7 inhibitors act by reinforcing the D1 signaling pathway, a pathway that is therapeutically relevant in human patients. However, in order to determine whether PDE7 is a valid clinical target, we need to understand the reason for our negative findings in the second pre-clinical model.
Objectives for Supplemental Investigation:
The current study will investigate possible reasons for our negative findings in the second MPTP model. One hypothesis is that the read-outs used in the second model does not respond via the dopaminergic D1 pathway as do those used in the first model (interestingly, human patients do respond to D1 agonists). Therefore, we will directly test the effects of D1 agonists on movement scores in these models and compare them to the effects of D2 agonists as well as L-dopa.
A second hypothesis is that the lengthy MPTP treatment of these pre-clinical models leads to downregulation of PDE7. We will therefore compare the levels of PDE7A and PDE7B between untreated and MPTP-treated pre-clinical models.
A less likely hypothesis is that our compounds failed to penetrate the blood brain barrier despite their efficient penetration into the rodent brain. Therefore, we will assess directly whether our drugs achieve sufficient levels in the brains of MPTP-treated pre-clinical models to inhibit PDE7.
Importance of This Research for the Development of a New PD Therapy:
We believe the importance of this research is two-fold. As noted above, an understanding of the divergent results in our two models is essential in order to determine whether PDE7 is a valid target in Parkinson’s disease. Because PDE7 inhibitors are not dopaminergic agonists, but act instead to reinforce the effects of endogenous dopamine, they present the possibility of improved safety and tolerability compared to L-dopa, resulting in an improved quality of life for patients.
The second aspect relates to the pharmacological properties of pre-clinical models models that are commonly used to test drug candidates. The usual progression from pre-clinical models to patient assumes that all respond in the same way to agents affecting dopamine signaling. However, studies that directly compare two different pre-clinical models are often lacking. The current study will constitute such a direct comparison and will, we hope, prove useful to other investigators in this field.
Final Outcome
We are testing a novel approach to the treatment of PD that entails the inhibition of the cellular enzyme PDE7. In parkinsonian pre-clinical models, this approach has been highly successful, but in the MJFF-funded study conducted by Omeros, other parkinsonian pre-clinical models failed to respond. In the current studies, we investigated possible reasons for this difference. We showed that our PDE7 inhibitor did enter the pre-clinical brain and that the PDE7 enzyme was present in both models. We did observe a difference in the way that these two models responded to levodopa, and this may be the cause of their difference in response to PDE7 inhibitors as well. Because the clinical response to levodopa appears to be somewhere between that of these pre-clinical models, only clinical studies can now determine whether PDE7 inhibitors will be effective in PD.