Targeting GCase with Novel Pharmacological Chaperones

Study Rationale:
People who have mutations in the GBA gene have a higher chance of developing Parkinson's disease (PD). The GBA gene encodes the glucerebrosidase (GCase) protein, an enzyme located inside the lysosomes, small intracellular vesicles in charge of the cellular cleaning mechanism. Changes in GCase affect several important cellular mechanisms and may contribute to neurodegeneration. To recover GCase activity, we propose to use small molecules called non-competitive pharmacological chaperones that specifically bind to GCase and help the mutant protein to recover its structure and stability, and consequently its activity.

Hypothesis:
We propose to recover GCase activity using non-competitive chaperones, which are brain-penetrant small molecules that bind specifically to GCase and facilitate the correct folding and processing of the GCase protein. These chaperones are able to promote GCase stabilization, increasing its enzymatic activity and reversing the deleterious effects caused by the mutation.

Study Design:
This project is being developed by two groups. First, the company Gain Therapeutics, focused on the development of non-competitive pharmacological chaperones, using computational chemistry techniques, has been able to design more than 400 potential non-competitive GCase chaperones. After an initial screening through biophysical and cellular-based assays, several compounds have been selected to be tested in PD cellular models by the second team: experts in PD and lysosomal dysfunction. Those compounds showing the most promising results will be further tested in models of PD/GBA with the goal to ease PD symptoms and pathology. The final objective is to select a drug candidate for future clinical studies.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
Using this therapeutic pipeline strategy, we aim to develop and validate new pharmacological GCase chaperones. Our compounds have been designed to cross the blood-brain barrier and are non-inhibitory chaperones, offering a wider therapeutic window.

Next Steps for Development:
If we succeed, we will select a GCase chaperone as a drug candidate to enter clinical trials for the treatment of Parkinson’s disease.