Pancreatic islet transplantation offers long-term treatment for Type 1 diabetes, however the shortage of donors and the need for immunosuppressive drugs restrict its therapeutic utility. Islet-like organoids generated from human pluripotent stem cells (PSCs) are an attractive alternative. Moreover, given the increasing appreciation for the role of multi-cellular organization in the functional maturation and maintenance of organs, islet-like organoids have the potential for superior functionality compared to ? cells alone. The goal of this project is to develop the next generation of human islet-like organoids (HILOs) from stem cells for efficient and immune evasive transplantation. The underlying hypothesis is that a combination of a novel 3D differentiation protocol, modulation of cell surface signaling, and anti-inflammation transcriptional machinery will enable HILOs to survive long-term and function in an immune competent environment in vivo. To achieve this goal, Aim 1 proposes to establish the long-term efficacy and safety profile of HILOs, of which the function has been validated extensively in vitro.
Aim 2 proposes to develop immune-tolerant HILOs by engineering the expression of PD-L1 and demonstrating the efficacy in humanized immune-competent diabetic mice. To further extend protection of transplanted HILOs, Aim 3 proposes to apply pharmacological activation of vitamin D signaling to alleviate cytokine stress on transplanted HILOs. The goal is to determine whether the incorporation of these strategies to improve survival as well as minimize allo-rejection of transplanted HILOs will result in an unlimited supply of therapeutically viable engineered islets for treating diabetes.

Public Health Relevance

The development of beta cell replacement therapies for diabetes offers promise for a long- lasting solution for type 1 diabetes. This proposal intends to combine cellular, molecular and pharmacological techniques to establish a robust protocol for stem cell-derived islet organoid transplantation. These novel methods will pave the way towards a clinical solution for insulin- dependent diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK120480-03
Application #
9970225
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2018-09-30
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037