This grant builds upon the research from a prior grant: Exploring the Use of Molecules that Stabilize the Interaction between LRRK2 Kinase and the 14-3-3 Adapter Protein as a Neuroprotective Therapy for Parkinson’s Disease
Progress Report
Study Rationale: The rationale to target leucine-rich repeat kinase 2 (LRRK2) as a therapeutic approach for Parkinson’s disease is well documented. Kinase inhibition of LRRK2 is well established and several specific and potent compounds have been discovered, including compounds that are currently in phase II clinical trial testing. Nevertheless, past experiences in other disease fields have taught us that it is risky to base hopes of success on a single therapeutic approach. In this project, we will explore alternatives for LRRK2 pathway targeting via LRRK2 modifiers.
Hypothesis: While targeting the LRRK2 pathway via LRRK2 modifiers is a promising approach, there is a pressing need for systematic studies to determine which LRRK2 modifiers are the most promising as therapeutic targets
Study Design: Our overall project goal is to establish a testing pipeline to systematically identify, characterize and carefully cross-validate potential LRRK2 modifiers via multiple approaches and by independent teams. This testing pipeline is organized in the following steps:
- LRRK2 modifier selection based on literature and data mining.
- LRRK2 modifier targeting via complementary techniques on a test set of candidate modifiers, including Bromo-Tag inducible knockdown, Lentiviral vector based knockdown and over expression (shRNA and CRISPRa) and interactor binding interface determination and targeting.
- LRRK2 modifier assessment under targeting conditions using molecular readouts of LRRK2 activity.
Impact on Diagnosis/Treatment of Parkinson’s disease: Since establishing LRRK2 as a priority therapeutic target in Parkinson’s disease, most therapeutic targeting programs have focused on developing strategies to target LRRK2 itself. By establishing and prioritizing targets of the same pathway, we open the path to perhaps more efficient or complementary therapeutic approaches.
Next Steps for Development: If successful, we will have an unbiased list of candidate LRRK2 modifiers and a validated testing pipeline. We will therefore be able to test all candidates in our pipeline and thus open the path to in depth therapeutic targeting of the best validated LRRK2 modifiers.