Advancing Bioengineered Production and Commercialization of the Novel Antidiabetic CompoundMontbretin-A

The Health Research BC Match Program is supporting a research program led by Dr. Joerg Bohlmann and his team at UBC, funded by GlycoNet (https://canadianglycomics.ca), a Canadian national research network focused on glycomics (the study of carbohydrates). The project includes international collaborators in The Netherlands and South Africa as well as industry and government partners in Canada. The PI is a professor and Distinguished University Scholar at the UBC Michael Smith Laboratories.  The team includes co-PIs with research and professional programs in chemistry, medicine and health care research and development. The project is developing a novel treatment option for type 2 diabetes (T2D), which is a defining disease of the 21st century affecting over 500 million people
worldwide, and predicted to increase to 1.3 billion by 2050. Control of blood glucose levels is key tomdisease manage-ment in T2D patients. Glucose levels are currently controlled with a combination ofmdiets, blood glucose monitoring, medication with potentially serious long-term side effects and insulin injections, all of which significantly impact quality of life. UBC researchers discovered that the plant natural product montbretinA (MbA) selectively inhibits the entry enzyme for starch digestion, the pancreatic alpha-amylase, resulting in effective control of blood glucose levels in animal models of T2D. They obtained Health Canada approval to move MbA through Phase-1 clinical trials as a novel treatment option for T2D. However, MbA is an extremely rare natural product that is only found in small amounts in montbretia (Crocosmia) plants, which is insufficient for commercialization. Furthermore, due to its
chemical complexity, MbA cannot be produced by chemical or chemo-enzymatic synthesis. To overcome this supply challenge and advance the commercialization of MbA, we are developing bioengineered production systems for MbA in yeast and the plant Nicotiana benthamiana (Nb). The innovation builds on over a decade of multidisciplinary research at UBC (Chemistry, Biochemistry,
Michael Smith Laboratories, Family Medicine) and Vancouver Coastal Health Research Institute. We previously discovered the complete MbA biosynthetic system using transcriptomics and metabolomics [Technology Readiness Level (TRL) 2]; established proof-of-concept MbA production in bioengineered yeast and Nb (TRL 3); in an industry partnership with PlantForm Corp. engineered industrial Nb lines for MbA production (TRL 4); developed an IP/patent portfolio around MbA applications and bioengineered
production systems (TRL 3); and launched Phase-1 clinical trials (TRL 4). In this project we will advance the MbA innovation and its commercialization to TRL 5 through four activities: Improve MbA yields in bioengineered production systems (Activity 1); optimize MbA purification protocols (Activ-ity 2); protect new IP (Activity 3); complete data analysis of a Phase-1 trial for safety and tolerability (funded by a previous grant) and design follow-up trials for efficacy (Activity 4). The anticipated outcomes are improved and scalable
bioengineered production systems and a scalable purification process for MbA (Activity 1 & 2); expanded IP protection (Activity 3); clinical trial data for safety and tolerability and approval and initiation of efficacy studies in T2D pa-tients (Activity 4). Achieving a defined set of milestones with each of the four activities will substantially derisk the MbA innovation and its commercialization for successful market entry. The outcomes will de-liver value to stakeholders, including patients and health care providers, and address a critical need in the treatment of T2D.