An inverse translational research project for identifying new treatments for Parkinsons disease: The Epi-screening project

We propose to carry out an initial screening of the approximately 800 most used drugs registered in the Norwegian Prescription database that contains all prescriptions for all Norwegians since 2004. We want to evaluate whether use of any of these drugs are associated with an increased or decreased risk of developing PD. In a second phase of the study, we will perform a number of sub-studies of the most promising drugs including studying the effect of doses and time between the use of these drugs and time of diagnosis of PD. The aim of these analysis is to disclose whether the associations we find are caused by PD patients using these drugs because of their PD disease - or whether the association reflects a real change in risk for developing PD. Finally, for the resulting list of candidate drugs we want to do a validation study using experimental models at a molecular level. We will dissect the mechanism by which these candidate drugs modulate PD-linked pathways in human neurons. Drugs that are validated in all three phases of the study are likely to represent reliable and plausible biological mechanisms relevant for the disease. As these drugs have a known safety profile, the results from this study could form a direct basis for phase-II clinical studies in humans. This could lead to novel treatment that may benefit those affected by diseases in considerable shorter time than in a more traditional drug development approach. We have now carried out the first screening of around 800 drugs. This has given us a list of 25 drugs that significantly reduce the risk of Parkinson's disease. In addition, we have created a list of 42 drugs that reduced the risk of Parkinson's disease by more than 30%, but that did not pass the test for multiple comparisons (adjusted p-value). For all these 72 drugs, we have evaluated dose-response effects, we have studied the time between the use of the drugs and the onset of the disease, and we have looked at whether there are differences in effect between genders. These first results have now been published in the journal Neurology where we show which drugs (at ATC-2 level, i.e. therapeutic subgroups) are associated with a reduced risk of Parkinson's disease - and which are associated with an increased risk. All these candidates (drugs) will now be validated with cell experiments at our collaborating laboratory at Harvard University in Boston. This work has started and the first results are ready. These are now being compared with the results from the screening of the Norwegian data, and an article based on this is now being prepared.

The aim of this project is to develop novel and effective treatments for Parkinson's disease (PD). To do this, we propose to conduct an innovative and cross-disciplinary project that will combine the extraordinary data source of Norwegian Health registries with experimental studies in collaboration with a world leading basic research environment. The proposed project represents a novel high-risk high-gain approach and has the potential to challenge current knowledge for the disease. We propose to carry out an initial screening of the 400 most used drugs registered in the Norwegian Prescription database, and to evaluate whether use of any of these drugs are associated with the risk of developing PD. In a second phase of the study, we will perform a "virtual" validation by carrying out a series of careful confirmation studies using a range of variables from the Norwegian Health registries. The main aim is to reduce false positives due to confounding. Finally, for the resulting list of candidates we want to do a validation study using experimental models at a molecular level. We will dissect the mechanism by which these candidate drugs modulate PD-linked pathways in human iPSC-derived neurons. Drugs that are validated in all three phases of the study are likely to represent reliable and plausible biological mechanisms relevant for the disease. As these drugs have a known safety profile, the results from this study could form a direct basis for phase-II clinical studies in humans. This could lead to novel treatment that may benefit those affected by diseases in considerable shorter time than in a more traditional drug development approach.