Award Partner: Pacific Parkinson's Research Institute

A chemical biology approach to uncovering modulators of a Parkinson’s disease-linked protein

Enzymes are biological machines which facilitate crucial processes in the human body. A reduction in the function of a given enzyme, sometimes brought about by an alteration or “mutation” to the underlying genetic code, often results in disease. In Parkinson’s disease (PD), a mutation in the GBA1 gene can cause earlier disease onset and rapid motor decline. Furthermore, the enzyme glucocerebrosidase (GCase) that is encoded by GBA1 is less active in PD patients regardless of whether they have a defective GBA1 gene. We hypothesize that GCase is altered or “modulated” by other proteins within the cell. My first goal in this project will be to create improved ways to measure the activity of GCase in live human cells. Previous work has shown that “ratiometric fluorescence sensors” – small molecules which light up when processed by a target enzyme – have high efficacy towards this end. The activity of a large library of existing drug candidates will then be tested for their ability to modulate GCase. Changes measured in GCase activity within cells treated with these drug candidates will help identify these aforementioned unknown “modulators”, thus revealing new insights into the mechanisms of PD and opening new therapeutic approaches.

Genome-wide screen to identify genetic modulators of glucocerebrosidase activity

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. Despite PD affecting millions of people worldwide, no disease-modifying treatment is available yet. As the progress of the disease is closely related to aging, improving our knowledge of the mechanisms and factors leading to PD is of great interest. Mutations in the gene GBA, which encodes the enzyme glucocerebrosidase (GCase), are the greatest genetic risk factor for PD. The link between GCase and PD however, remains poorly understood. Here, we propose to use a chemical genetic screening approach to identify new genes that affect GCase activity. As a pilot study, we will target known PD-associated genes and evaluate their effects on GCase activity using a new GCase activity-based assay in live cells. A complementary approach using genome-wide screen will be carried out to identify candidate genes in an unbiased way. Candidate genes from these screens will be validated with downstream experiments leading to two valuable outcomes. First, the discovery of new genes that regulate GCase could provide new targets for potential treatments. Second, we expect these findings will uncover new fundamental understanding regarding the mechanisms contributing to PD.

3D bioprinting personalized neural tissues for drug screening

Bioprinting can produce living human tissues on demand, opening up huge possibilities for medical breakthroughs in both drug screening and developing replacement tissues. The Willerth lab was the first group in the world to use the cutting edge RX1 bioprinter from Aspect Biosystems to bioprint neural tissues similar to those found in the brain using stem cells derived from healthy patients. Similar tissues can be printed using stem cells derived from patients suffering from Parkinson’s disease, recapitulating the disease phenotype in a dish. These highly customized, physiologically-relevant 3D human tissue models can screen potential drug candidates as an alternative to expensive pre-clinical animal models.

 

This project will bioprint both healthy and diseased neural tissues using our novel bioink in combination with Aspect Biosystems’ novel trademarked Lab-on-a-Printer system and evaluate their function. We will then validate these tissue models as tools for drug screening by exposing them to compounds with known toxicity to brain tissues.

 

Dr. Stephanie Willerth has over 16 years of experience in the area of biomaterials and tissue engineering, making her the ideal choice to lead this project. This project will lead to better health outcomes for patients suffering from neurological diseases and disorders, which account for 6.7 percent of the healthcare burden in Canada and improve the quality of life for BC residents suffering from such diseases.

End of Award Update: December 2022

 

Most exciting outputs

We developed a prototype of our BrainPrint bioink for bioprinting human brain tissue models. This ink makes it easy to use a 3D bioprinter to generate human brain tissues in a rapid and reproducible fashion.

 

Impacts so far

The project led to the creation of Axolotl Biosciences – an award-winning spin-off company – that is commercializing BrainPrint with the goal of a product launch in 2023.

 

Potential future influence

We are currently using BrainPrint to generate models of Parkinson’s disease and Alzheimer’s disease.

 

Next steps

We are building upon this work in lab to further characterize our neural disease tissue models. Axolotl is beta testing BrainPrint with users from across British Columbia.

 

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