Project 457194

Type 1 diabetes (T1D) is a debilitating disorder affecting millions of Canadians, generally from childhood. Patients with T1D lack functional beta cells that release insulin, making cell replacement approaches a highly effective treatment. The Edmonton Protocol made breakthrough improvements for transplanting clusters of islets, containing beta cells, into patients. However, widescale adoption of this treatment has been limited by availability of cells from recently deceased donors. Since their discovery over 20 years ago, human pluripotent stem cells (hPSCs) have opened the door to producing off-the-shelf cell therapies. hPSCs are special cells that can multiply and also become all cell types of the body. Canadian leaders like Dr. Timothy Kieffer have uncovered ways to produce maturing beta cells from hPSCs. Since these discoveries, exciting clinical trials are underway in which these beta cells are loaded into thin devices and implanted under the skin. While initial results are encouraging, for beta cell therapy to be available for children with T1D, we need reproducible bioprocesses to make trillions of hPSC-derived beta cells on-demand. To tackle this unmet need, we will use an interdisciplinary approach spanning stem cell biology and bioengineering. Our goal is to understand how each hPSC and its progeny (a “clone”) multiplies and differentiates to produce beta cells. To do this, we will expand on our existing cutting-edge genetic toolset to track and control hPSC clones, allowing us to: identify “bad” clones that acquire culture-induced mutations and plague the safety of the cell batch, while studying the mechanisms that allow “good” clones to become functional beta cells. By unlocking clonality as a new bioengineering tool, we will improve the safety, efficiency, and purity of beta cell therapies. With support from clinical and translational partners, we seek to facilitate made-in-Canada production of beta cells, freeing children from insulin injections.