Brain disorders affect 10% of Canadians, however few treatment options exist for these devastating diseases. We have extensive understanding of what causes many of them, but current medical technology has yet to translate this knowledge into effective treatments. For example, many natural proteins have been identified to hold significant therapeutic promise, but getting these proteins to the brain has been a longstanding challenge. Our group has developed a technology that empowers the brain to produce its own therapeutic proteins to treat brain disorders. Using a technology similar to the COVID vaccine that combines lipid nanoparticles (LNP) and messenger RNA (mRNA), we can transform brain cells into protein factories that continually produce these therapeutics proteins over days to weeks. We have proof of concept data in mice demonstrating this strategy is tunable and achieves long lasting brain-wide biodistribution of desired proteins, requiring fewer infusions compared to existing treatments.
The proposed collaboration with the MacVicar Lab at UBC is to develop an LNP-RNA based treatment for Gaucher Disease (GD, Types I-III). GD is a rare lysosomal storage disorder caused by mutations in the GBA gene coding for the vital enzyme Glucocerebrosidase (GCase). GCase deficiency in GD manifests as a spectrum of brain disease, from rapid neurodegeneration and death in infancy or early childhood (Type II), to saccade eye movements to epilepsies, to dementia (Type III). Even Type I, which is often considered ‘non-neuronopathic’, has been shown to be strongly correlated with Parkinson’s disease and related neurological symptoms. GD Types I and III are treated with biweekly intravenous infusion of Imiglucerase (Cerezyme®), an enzyme supplement for GCase. However, Imiglucerase has no impact on neurological symptoms in GD because it does not reach brain tissues.
We propose to use our Bioreactor strategy to manufacture GCase directly in the brain as a treatment of neurological GD. Our group uses brain-optimized LNPs to achieve widespread LNP-mRNA uptake in disease-agnostic cells in the central nervous system to transform them into Bioreactor cells. These Bioreactor cells will translate the mRNA into functional GCase, which is released to the entire brain to effectively replace the dysfunctional GCase that causes GD. As a first step, we must engineer GCase mRNAs for optimal GCase production and longevity in Bioreactor cells. The intern, Dr. Daniel Andrews, a trained mRNA biochemist, will conduct key studies in cell culture models to generate optimized mRNA constructs for GCase. This work will be split in four Aims; (1) to establish a reliable cell culture system to produce and test mRNAs for GCase, (2) to engineer mRNA sequences for GCase to optimal expression in these cell cultures, and (3) to compare the enzymatic function of GCase from different mRNA constructs produced in cell cultures to identify lead candidates for animal testing, and (4) encapsulate mRNAs into LNPs for brain injections in mice.
Dr. MacVicar has over 37 years of experience as a neuroscientist with a proven track record of training young scientists that go on to faculty positions in academia, medicine, industry, and government agencies. Dr. Andrews will work closely with neuroscientists in the MacVicar laboratory, where he will develop expertise in the field, as well as technical training on state-of-the-art laser imaging microscopes. Dr. Andrews will also be directly involved in training and mentoring students in the lab to further develop his leadership skills. Dr. MacVicar’s ongoing collaborations with Dr. Pieter Cullis, a world leader in LNP-based nanomedicines, will position Dr. Andrews at the forefront of next-generation therapeutic development, with access to UBC’s vast network of RNA and nanomedicines experts and ability to produce high quality research. Dr. Andrews will also be exposed to a breadth of training opportunities at CCNTx that would only be possible at a small startup company. Dr. Andrews will be directly involved in higher-level R&D and IP planning related to CCNTx operations. This will include participating in IP strategy, forward-looking research objectives, business development activities, and attending industry conferences. This will place Dr. Andrews in a position to contribute both to the R&D and the growth of the company during its formative stages.
CCNTx is a UBC spinoff company and technology transfer partner. The data generated by the project is likely to generate new intellectual property (IP) that will be further developed by CCNTx for future commercialization. As a startup company, building an IP portfolio will be critical for future success and attracting future investment and partnership with large pharmaceutical companies. This will be vital for the near-term growth of CCNTx, which will also lead to job creation in the Vancouver biotech ecosystem and training for highly qualified personnel.