Developing a personalized approach to beta cell replacement for patients with a genetic form of diabetes

The long-term goal of this study was to generate a patient-specific stem cell line that would be capable of generating functional insulin cells that could be used as a potential cell translate therapy in the future.  We focused on correcting a mutation in am index patient's DNA that prevented this patient from making functional insulin cells able to sustain normal blood sugar levels.  We collected the patient's skin cells and converted the skin cells into induced pluripotent stem cells.  We attempted to differentiate the induced pluripotent cells into insulin cells in the lab, but it did not work. To make the induced pluripotent stem cells capable of making insulin cells, we used CRISPR-Cas9 gene editing to fix the patient's mutation in the induced pluripotent stem cells.  Once the mutation was fixed, we pursued experiments that proved that the corrected induced pluripotent stem cells were now capable of differentiating into insulin cells that can release insulin in response to high glucose levels.  

To our knowledge, this is the first project to correct a patient's gene mutation that restored the patient's cells ability to make functional insulin cells.  We are currently writing this research project up for publication in a widely read scientific journal.  We are preparing a CIRM DISC2 application to continue this project.  The first step was to establish that we could restore the capacity of the patient's cells to differentiate into insulin cells.  Our next step, as will be proposed in the DISC2 application, will be to  scale up production of the patient's insulin cells and prove that they can cure diabetes in larger animal models more reflective of human diabetes.  We have also identified 3 other patients at our institution that could benefit from a potential insulin cell therapy for their diabetes, and we will propose experiments to create a pipeline that creates personalized induced pluripotent stem cells able to produce insulin for patients with diabetes.