Because animal models have limited predictability for clinical outcomes of experimental Parkinson drugs, a complex mathematical model of the interactions between key motor pathways has been developed, based upon pathological and physiological information from human subjects. In addition we use the clinical information from different neuroleptics-induced Parkinonism in schizophrenia patients to identify possible new non-dopaminergic targets. We plan to ‘virtually’ screen approved CNS active drugs to identify possible candidates for a clinical study.
The virtual effect of 23 different membrane targets has been implemented in this mathematical model using pre-clinical biophysical data and human imaging data. Actual functional drug concentrations are determined from available clinical PET imaging studies by simulating displacement of a radio-active tracer at the receptor. Unlike the traditional animal models, we have validated this model of antipsychotics-induced Parkinsonism by calculating the correlation between the model outcome of 51 drug-dose combinations and their clinical effects, resulting in a five-fold higher correlation compared to the simple D2R occupancy rule. We will optimize this model by introduction of the Parkinson’s pathology and subsequent validation with existing clinical data. We will then screen the existing CNS active drugs on the market to identify possible candidates for a fast Proof-of-Concept study.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This is a search for novel non-dopaminergic targets within the profiles of existing and currently marketed CNS active drugs, using complex mathematical framework as a model embedded with human pathology and motor-related clinical scales.Insights from this study could both alleviate symptoms of Parkinson’s disease and drive a better understanding of the pathology.
Unlike the classical animal models, this model is situated much closer to the human disease situation and validated using a large clinical database. We anticipate this project to identify novel cortical targets and existing CNS active drugs on the market which engage these targets. If successfully, the outcome would include the proposed design of a small clinical proof-of-concept study.
Dr. Geerts and his team have developed a computer-based disease model for testing pharmacologic modulation of the serotonergic and dopaminergic systems. After screening a large number of approved and marketed compounds in this model, five drugs have been identified that could have a beneficial Symptoms & Side Effects effect in treating Parkinson’s disease.