Study Rationale:
Beta-glucocerebrosidase (GCase), a protein that processes some of the key components of cell membranes, is required for normal brain function. Reduced activity of this protein increases the risk of developing Parkinson’s disease (PD). While some people with PD have genetic mutations that impair the function of GCase, in the majority of cases, the mechanism that causes this loss of activity is unknown. Although drugs that restore GCase activity would likely prove useful for the treatment of PD, the efforts to develop such therapeutics have thus far been unsuccessful.
Hypothesis:
Arkuda Therapeutics has discovered compounds that enhance the activity of GCase in cells. In this study, we will test the ability of an Arkuda compound to increase the activity of GCase and reverse the molecular markers of PD in cell and preclinical models of the disease.
Study Design:
We will first determine if the Arkuda compound can boost GCase activity in mouse neurons, in human neuron-like cells and in immune cells isolated from people with PD who have mutations in GCase. We will then assess whether the Arkuda compound rescues the molecular changes in a cell model of neurons that carry mutated GCase. Finally, we will determine if the Arkuda compound increases GCase activity in a preclinical PD model bearing a GCase mutation and identify substances in the blood, spinal fluid and urine whose concentrations change in response to treatment.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
A compound that increases GCase activity will be an effective treatment for PD that is caused by mutations in this protein — and potentially for the larger PD population. If successful, this project will advance a new and exciting treatment approach for PD.
Next Steps for Development:
The compound to be tested in this study has already completed initial safety testing in pre-clinical models of PD. If it proves to be effective in the cell and pre-clinical models used in this project, a related compound could be advanced quickly to human clinical testing.