Funded Studies
Study Rationale:
The majority of cases of inherited Parkinson’s disease (PD) are caused by a single-letter change in the gene that encodes the LRRK2 protein. The mutation, which changes a G to an A, produces a hyperactive variant of the LRRK2 protein. This overactive protein, known as G2019S, disrupts the normal function of the brain cells and ultimately leads to PD. Recently, we developed a new way to repair G-to-A mutations using molecules called short antisense oligonucleotides (ASOs). These recognize the mutated sequence and recruit a protein called ADAR, present in human cells, to perform the repair.
Hypothesis:
We hypothesize that our approach — using ASOs to recruit the repair protein ADAR — will provide a promising therapeutic approach to correcting the G2019S mutation in LRRK2 and restoring its normal function.
Study Design:
First, we will optimize the design of ASOs capable of efficiently repairing the LRRK2 G2019S mutation by testing hundreds of thousands of different ASOs in human cells. The top candidates will be tested in cells derived from people with PD, where we will assess whether these ASOs can decrease the protein aggregation that is characteristic of PD. At the same time, we will try different approaches to deliver ASOs to the brain in a pre-clinical PD model. We will then determine whether the ASO can restore the normal function of LRRK2 in the brain and diminish the symptoms of PD.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our ASO-based approach holds the potential to restore healthy levels of LRRK2 activity in people carrying the G2019S mutation; we expect this molecular repair to suppress or even fully eliminate PD symptoms.
Next Steps for Development:
After establishing the efficacy of our approach in pre-clinical models and in cells derived from people with PD, we will move the resulting ASOs into clinical development, optimizing their drug-like properties and establishing an effective dosage and frequency of delivery and confirming their safety in humans.