Objective
The "SMART-ISLETs" project seeks to advance the treatment of type 1 diabetes by enhancing the resilience of insulin-producing cells which play a vital role in blood sugar control. Type 1 diabetes is characterized by the immune system's attack on these crucial pancreatic cells, resulting in insulin deficiency. Currently, when these cells are transplanted into diabetic patients, many do not survive, limiting the treatment's effectiveness. Our project employs two key approaches to address this challenge. First, we will utilize advanced genetic techniques to make these insulin-producing cells "smarter" to withstand transplantation-related stressors. In particular, we will target specific genes, PTPRF, PTPRK, and TXNIP, to empower these cells to thrive under adverse stress conditions. Second, we will explore the use of pharmacology to further improve the survival and function of these insulin-producing cells after transplantation. Ultimately, our objective is to enhance the success rate of islet transplantation, reduce the reliance on donor cells, and offer a more personalized and effective treatment approach for patients with type 1 diabetes.
Background Rationale
Existing type 1 diabetes treatments struggle to protect and preserve insulin-producing cells.
One promising approach is islet transplantation, in which insulin-producing cells are transplanted into diabetic individuals. However, this method faces significant challenges. These include islet cell exhaustion, donor islet shortage, and the necessity of lifelong immunosuppressive therapy to prevent rejection. In addition, various stress factors, such as high blood sugar, inflammation, and oxygen deficiency, negatively affect the success of islet transplants. Recent advancements in the creation of insulin-producing cells from stem cells offer hope for addressing these challenges. However, significant hurdles remain. The "SMART-ISLETs" project has been designed to tackle these issues head-on. Its primary objective is to enhance the resilience of insulin-producing cells when transplanted into individuals with type 1 diabetes. The underlying rationale is that by modifying specific genes (PTPRF, PTPRK, and TXNIP) and employing targeted pharmacology, these cells can be improved to better withstand the stresses encountered post-transplantation. This study aims to significantly improve the viability and function of these cells during and after transplantation. Ultimately, the rationale for this project is driven by the pressing need to improve the effectiveness of islet transplantation, reduce dependence on donor cells, and provide a more personalized and efficient treatment option for patients with type 1 diabetes.
Description of Project
Type 1 diabetes typically affects young individuals when the immune system mistakenly attacks and destroys vital insulin-producing cells , known as β cells, in the body. The SMART-ISLETs project focuses on enhancing the effectiveness of islet transplantation, which involves replacing these crucial insulin-producing cells in individuals with T1D to help them regulate their blood sugar levels. Our recent discoveries indicate that a group of proteins known as “protein tyrosine phosphatases” play a direct role in the fate of pancreatic β cells in type 1 diabetes. Some members of this group of proteins have been identified as candidate genes for the development of the disease. The project intends to enhance the resilience of artificial islet cells derived from human stem cells through genetic modifications of these selected candidate genes, thereby making them better equipped to withstand the challenges of transplantation. By combining cutting-edge genetic editing techniques, this study aims to enhance the function and survival of transplanted islet cells. In this study, we provide a detailed exploration of the role of protein tyrosine phosphatases in the mechanisms determining β-cell function, survival, and death after transplantation. In addition to genetic enhancements, the project explores the use of new drugs that target candidate genes, including verapamil, to protect islets after transplantation. These drugs are designed to shield cells from damage induced by different stress factors. A successful outcome of this project could lead to an improvement in the treatment of type 1 diabetes. By strengthening islet cells and enhancing their resilience after transplantation, we hope to achieve a better outcome.
Anticipated Outcome
The anticipated outcome of this research study is the development of more resilient islet cells that can better withstand transplantation stresses and provide improved long-term control of blood glucose levels in pre-clinical models of type 1 diabetes. This could lead to a significant improvement in the transplantation protocol and our understanding of the disease. Furthermore, our approach can improve existing methods such as encapsulation, which creates a protective shield around artificial insulin-producing cells.
Relevance to T1D
In this proposal, we will delineate the unexplored role of our recently identified candidate proteins for type 1 diabetes. The project is directly relevant to the disease because it addresses one of the core problems in its treatment, specifically, the loss of insulin-producing cells. By improving islet cell transplantation outcomes, this study has the potential to provide a more effective and durable solution for managing the disease. The "SMART-ISLETs" project aims to improve the limitations of current type 1 diabetes treatments. Islet transplantation faces obstacles such as a shortage of donor islets, the need for lifelong immunosuppressive medications, and the early loss of transplanted insulin-producing cells due to different stressors. The present project is designed to create insulin-producing cells with enhanced resilience for transplantation. By targeting specific genes and using innovative medications, this study aims to boost the overall success of islet transplantation.