Study Rationale: Activating mutations in LRRK2 are a common cause of Parkinson’s disease (PD). We propose using aptamers to inhibit LRRK2. Aptamers are snippets of DNA or RNA that can fold into shape that allows them to bind to a specific region of a target protein, such as LRRK2, making them more effective inhibitors even in complex cellular environments. Aptamers also cross the blood-brain barrier more readily than small molecule inhibitors. In this study, we aim to increase the stability of our aptamers through strategies like circularization and dual aptamers, potentially leading to improved therapeutic efficacy against LRRK2.
Hypothesis: We hypothesize that aptamer-based LRRK2 inhibitors that function by binding to different parts of the protein will effectively modulate LRRK2 activity and be delivered selectively to the brain.
Study Design: We will identify aptamers against LRRK2 and evaluate them for function and selectivity. These best aptamers will be optimized for improved targeting and stability.
Impact on Diagnosis/Treatment of Parkinson’s disease: PD therapeutics could benefit from the development of modalities other than small molecule kinase inhibitors. The aptamers we identify can be used for both diagnostics as well as treatment, particularly if those that bind outside LRRK2’s kinase domain demonstrate significant improvements.
Next Steps for Development: Aptamers that have good stability and activity in a test tube will be optimized for function in cells, enabling development for clinical studies. This optimization will include nucleotide replacement and formulation strategies including (but not limited to) the use of lipids, nanoparticles and bioconjugation.