Objective
The objective of this proposal is to generate a cell therapy product that can not only replace the endogenous pancreatic islet insulin-producing beta cells, the cohort of cells lost upon autoimmune attack in type 1 diabetes, but also be monitored at an accessible site through non-invasive means once grafted into patients. The organoids we generate will secrete insulin in a glucose-responsive manner, and will have biosensors within them that serve as beacons of information allowing surgical teams to develop interventional therapies to improve the longevity of the grafts.
Background Rationale
Whole pancreas transplantation or cadaveric donor islet infusion into the portal vein are the only current therapies to achieve long-term insulin independence in patients; stem cell-derived therapies (including those led by ViaCyte and Semma/Vertex) have reached early-stage clinical evaluation, de-risking challenges such as dosage and safety of transplanted cells and paving the way for moving these products to market; Minutia is the next generation of such transplants. Replacement therapy continues to suffer from challenges in the immediate post-transplantation period including reduced oxygen in the surrounding environment, damage from molecular secreted by immune cells, and inflammation due to contact with large quantities of blood, among other undesirable events. Furthermore, current transplantation success is variable, with C-peptide levels and glucose measurements used as readouts of cell function, parameters that have a significantly delayed onset. There is a clear need to improve the methods for evaluating graft health, as currently patients receiving islet cell therapy need two, sometimes three infusions to achieve insulin independence. Visualizing distressed cells within a graft provides a unique opportunity to either replace with more cells before loss of glucose regulation, or, more importantly, administer local therapies that can reverse the effects of the damage inflicted upon the graft in the critical period following transplantation.
Description of Project
We combine two foundational technologies to improve cell therapy outcomes in patients with Type 1 Diabetes (T1D). By engineering human stem cell derived insulin-producing cells with biologically responsive sensors for transplantation therapy, we achieve two goals: generate high quality cells to replace the cohort of insulin-producing cells that is lost in patients with T1D, and develop “sensing” cells that emit a signal as a result of a biological activity within the cells, providing a cue for timely intervention that can save failing grafts. We propose that human stem cell-derived insulin-producing cells incorporated with such biosensors can change the landscape of how we measure post-transplantation success. Instead of waiting weeks or even months to measure C-peptide from the grafts, our technology promises to provide information regarding graft health immediately after introduction into the recipient, and presenting an opportunity to develop an interventional therapy to counter some of the roadblocks that face transplants. Our technology literally shines light on the black box that is the acute post-transplantation period – highlighting adverse events that influence the longevity of the graft. Allogeneic islet cell transplantation is plagued with numerous challenges, and it is paramount that future technologies address these issues without placing the burden on patients (such as systemic immunesuppressive regimens that come with significant side effects).
Anticipated Outcome
Real-time monitoring of cell health and function in T1D patients who receive cell therapy has remained elusive. Today, the final graft site of donor islets or stem cell derived organoids that are infused into the portal vein remains unknown; these cells disperse through the hepatic parenchyma and several are lost due to inhospitable locations. To improve the success rate of this approach, Minutia is developing a novel therapeutic product that incorporates stem cell technology and biosensors to make cell grafts visible within the body, and such visibility relies on specific changes that occur within cells in response to their niche. We propose to address the challenges faced by transplanted cells using our technology; we also explore a different transplantation site, for greater accessibility and to circumvent some of the challenges associated with current graft sites. We anticipate that our product will make visible the graft after it has been introduced into patients; we will also be able to measure if the graft is failing, and be able to intervene and reverse the damage pre-emptively, with the long term goal of insulin independence in all patients receiving cell grafts.
Relevance to T1D
Our long term goal is to develop a therapeutic product that can sense a failing graft due to an inhospitable niche long before secondary readouts such as reduced C-peptide levels and dysglycemia, allowing for timely interventions by surgical teams to save graft function, improve transplantation success, and extend the duration of insulin independence in patients with Type 1 Diabetes (T1D).