Objective
The Objective of this research is to improve ways to assess how well transplants of insulin-producing cells made from stem cells are working. To do this, we will apply new assays that allow the measurement of proteins made by beta cells in just a few drops of blood and use these measurements to assess the function of transplanted insulin-producing cells made from stem cells.
Background Rationale
Replacement of insulin-producing cells by transplantation of islets from pancreas organ donors or made from stem cells has great promise as therapy to restore insulin production in T1D. Insulin-producing cells made from stem cells could provide an unlimited source of cells for transplantation for the millions living with T1D. As stem cell therapies rapidly move forward towards more clinical trials in T1D, there is an increasing need to find the best ways to measure the function of transplanted cells so that researchers can best understand why some transplants fail and some succeed. One measure of the function of insulin producing cells that has been explored for use in T1D and islet transplants is the measurement of large forms of protein hormones that are made by insulin-producing beta cells when they make insulin. Elevated amounts of these so-called prohormones can be indicative of cells not doing well. Researchers on this team have expertise in stem cells, transplantation, and the measurement of prohormone forms, and here propose to test whether measurement of these prohormones in models of stem cell transplantation in T1D could improve assessment of how well these transplants are working and, in doing so accelerate stem cell therapy research and clinical trials in T1D.
Description of Project
Replacement of insulin-producing cells by transplantation has potential as a potential curative therapy for T1D but is limited by supply of pancreatic islet donors and long term graft survival and function. Stem cells offer hope for an unlimited supply of insulin-producing cells that could provide insulin replacement and restore glucose control for persons with T1D. As stem cell-derived insulin-producing cells move into clinical trials in T1D, we need ways to assess how well these cells are functioning and surviving following transplantation. Current approaches to measure stem cell transplant function are somewhat limited and include blood glucose control and release of C-peptide in response to a meal, a measure of how well beta cells are working. Breakthrough T1D has recognized the need for non-invasive and simple ways to assess the function of transplanted stem cell derived insulin producing cells in persons with T1D. Here we propose measurement of proteins made by insulin-producing beta cells and that can be detected in human blood as alternate measure of stem cell transplant function. The proteins are called prohormones, and they are the parent proteins from which insulin and another hormone made by beta cells, called IAPP, are made. Our team has developed ways to measure the small amounts of these prohormones, called proinsulin and proIAPP, in just a few drops of blood. In this proposal, we hope to show that measurement of prohormones made by stem cells-derived insulin producing cells could be an alternative and informative measure of stem cell transplant function. We will measure secretion of these proteins from stem cell derived insulin producing cells under different conditions, including following their transplantation into a pre-clinical mouse model of T1D. We will compare these prohormones under different transplant conditions, specifically after transplantation of these cells into different sites in the body used clinically, including muscle and eye. If successful. our goal is to move this approach to the clinic, and to add prohormone measurement to the ways in which we can assess stem cell transplant function in persons with T1D, with the long-term goal of improving this promising cell therapy for the many living with T1D around the world.
Anticipated Outcome
We anticipate that this research will lead to new and more insightful ways to assess how well insulin-producing cells made from human stem cells are functioning after transplantation, complementing current measures to assess how well stem cell therapies are working.
Relevance to T1D
This research has the potential to benefit person living with T1D and who may receive cell therapies of insulin-producing cells made from human stem cells. The goal is to improve approaches to assess how well these transplanted cells are functioning and allow us to better compare how well different transplant approaches are working, for example when insulin-producing cells made from stem cells are transplanted into different sites in the body or inside different encapsulation devices. By providing a better measure as to how these transplanted cells are working under different conditions, this research could accelerate the improvement of stem cell therapies to benefit more people living with T1D.