Study Rationale: Some forms of Parkinson’s disease are caused by inherited mutations in the LRRK2 gene, and these mutations change the LRRK2 protein in such a way that it becomes too active. The LRRK2 protein can be deactivated by inclusion of pseudoexons into the LRRK2 transcript, which would otherwise produce normal protein. With splice-switching oligonucleotides (SSOs) we can stimulate the inclusion of these pseudoexons with high precision and effectiveness. Because the LRRK2 protein is important, it is also important not to remove the protein completely and pseudoexons can be activated in such a way that normal LRRK2 protein can still be produced.
Hypothesis: The use of SSOs to activate insertion of pseudoexons into LRRK2 transcript and thereby deactivate the hyper-active LRRK2 protein that causes Parkinson’s disease offers a robust and attractive therapeutic strategy because the oligonucleotides can be designed to be both safe, highly selective for mutant LRRK2, and very effective.
Study Design: We have designed preliminary versions of the SSOs and in this project we will further optimize these to obtain more effective SSOs that are clinically safe to use and of high therapeutic value. We will use patient cells grown in the lab to test new SSO designs that are optimal for use in humans and we will use mouse models to check for therapeutic efficacy. We will also use cells from Parkinson’s disease patients to generate neurons and small neuronal structures that we can then use to demonstrate the therapeutic activity and value of the best SSOs.
Impact on Diagnosis/Treatment of Parkinson’s disease: The development of clinically safe and highly therapeutic splice-switching oligonucleotides holds the promise of novel treatment options for patients with Parkinson’s disease that either have a LRRK2 activating mutation, or where deactivation of LRRK2 is beneficial to their continued life with Parkinson’s disease.
Next Steps for Development: Following the development of SSOs and tests in animal models, it will be necessary to conduct clinical trials, first in healthy people to confirm safety of the treatment, and then in people living with Parkinson’s disease to demonstrate a clinical benefit when given the treatment.