Proof of Concept and Translational Validation of USP30 to Offset Dysfunction in the PRKN Pathway

Study Rationale: 
USP30 is an enzyme which acts in the opposite way to Parkin (PRKN), a gene linked to young-onset Parkinson’s disease (PD). Mutations in the PRKN gene impact mitochondria (the cell’s powerhouse). This could lead to mitochondria dysfunction, which may play a role in cell death, causing Parkinson’s symptoms and progression. Inhibiting USP30 might help offset this dysfunction. At Mission Therapeutics, we believe that USP30 inhibition could be a good therapeutic approach for people with young-onset Parkinson’s disease and Parkin or PINK1 mutations, and that this mitochondrial improvement mechanism could be broadly applicable to other forms of Parkinson’s disease.

Hypothesis: 
This study will investigate whether USP30 inhibitors can protect from degeneration of dopamine-containing cells in a pre-clinical model with young-onset PD.

Study Design: 
We will be giving pre-clinical models USP30 inhibitors for a duration of four months and then will assess whether dopamine-containing cells have been protected. We will use different amounts of USP30 inhibitor to see if positive effects are related to different amounts of the drug. We will also determine whether USP30 inhibitors affect other biomarkers which are present in people with PD and PRKN mutations, hoping to further increase the meaningfulness of using these pre-clinical models for translational studies and early clinical trials.

Impact on Diagnosis/Treatment of Parkinson’s Disease: 
If our USP30 inhibitor can protect dopamine-containing cells in pre-clinical models, we believe that people with PD and PRKN mutations may benefit from USP30 inhibitor treatment. Furthermore, repeating human biomarkers in pre-clinical models would validate use of this model as a useful translational tool and could help provide response biomarkers to measure in early clinical trials.    

Next Steps for Development:
If outcomes are positive, and our USP30 inhibitor also passes parallel safety testing, we will progress our inhibitor into human trials, confirming that enough USP30 inhibitor gets into the human brain, before progression to human biomarker/efficacy trials.