Study Rationale: Currently, drug discovery efforts for neurodegeneration are almost exclusively focused on disease risk, not the progression biology that afflicts patients when they present with symptoms decades after the pathologies started in the brain. Using artificial intelligence and detailed analysis of gene and protein networks relevant to the disease biology we have identified novel targets that drive Parkinson’s disease progression. One of these targets, which is present in 20-30% of PD patients, is the focus of our novel drug discovery efforts.
Hypothesis: We have started with human data and identified a target, with genetic and biochemical biomarkers, that has the potential to slow Parkinson’s disease progression in a specific subset of patients enabling a precision medicine approach to this disease.
Study Design: We will accelerate the medicinal chemistry program to generate new molecules, using an AI/ML approach. In parallel, we will use new technologies to grow up to 100 of the PPMI iPSC cell lines together pools and then determine how stressors, including aging the cells in the dish, affect the cell viability related to their known genetic and clinical status (e.g. fast vs. slow progressors). The susceptible lines will be used to evaluate the novel small molecules in a ‘clinical trial in a dish’. Finally, we will use sophisticated alpha-synuclein models to understand the underlying mechanisms of the disease and to understand biomarkers that have been associated with the pathways that we have linked to the faster progressors.
Impact on Diagnosis/Treatment of Parkinson’s disease: Clinical studies will be enabled by the genetic and biomarker stratification of the fast-progressors which represent 20-30% of PD patients and are predicted to respond to the specific therapeutic that we are developing.
Next Steps for Development: At the end of the project, we will have accelerated the medicinal chemistry efforts to provide new molecules and assays to support the accelerated lead optimization to bring a novel therapeutic into the clinic.