Study Rationale:
LRRK2 gain-of-function gene mutations (R1441C and G2019S) are one of the most prevalent mutations contributing to inherited Parkinson's disease (PD). Altered LRRK2 function has also been linked to sporadic PD (no known cause). Increased LRRK2 kinase (protein regulation) activity has been linked to altered mitochondrial health (powerhouse of the cell), axon outgrowth (cell communication sites), intracellular trafficking (movement of parts in the cell) and autophagy (breakdown of parts in the cell) in PD pre-clinical models. The use of antisense oligonucleotide (man-made molecules; ASO) aims to induce a long-term decrease in expression of this protein kinase to reduce kinase activity as a therapeutic treatment.
Hypothesis:
The main hypothesis of this therapeutic approach is to directly and chronically decrease LRRK2 kinase activity by editing out the parts of the gene known to contain two major mutations, R1441C and G2019S.
Study Design:
This project will design and develop improved ASO sequences. The validity of these newly designed ASOs and the functionality of their chemical changes will be tested in samples from participants with PD carrying these LRRK2 mutations. The target engagement of the two most promising ASO sequences will be tested in pre-clinical models. The final evaluation of the selected ASO will be based on its efficiency for target engagement and reduction of the kinase activity in a PD pre-clinical model.
Next Steps for Development:
Following successful completion of this proposal, we will seek further resources to continue advancing this therapeutic strategy toward clinical application.
Impact on Diagnosis/Treatment of Parkinson's disease:
Through this unique and novel approach, we can develop a long-term, effective and stable therapeutic treatment decreasing LRRK2 kinase activity and alleviating LRRK2-associated neuronal dysfunction in PD.