Objective
Our long-term goal is to cure type 1 diabetes (T1D) through beta cell replacement therapy, which uses cell transplantation to restore the insulin-producing function that is lost in patients with T1D. In beta cell replacement therapy, current urgent needs are to find an alternative source of insulin-producing cells to address an existing donor shortage, and to find an optimal transplantation site. Induced pluripotent stem cells (iPSCs) are a potential alternative source for insulin-producing cells, which can be transplanted into the subcutaneous (SC) tissue under the skin, the only approved site for stem cell-derived insulin-producing cells. Toward our long-term goal, our objective in the proposed project is to improve transplantation of human iPSC-derived insulin-producing cells in animal models using our novel Mesh Oxygen Transporter in the SC site. The SC site is “hostile” to transplanted cells due to a lack of oxygen, which makes it difficult for a cell graft to survive and function. We developed the Mesh Oxygen Transporter to transport oxygen from the room air to the SC site, avoiding the need for chemicals or electricity to generate oxygen. In this way, it will transform the hostile SC environment into a graft-friendly, oxygen-rich site, which we expect to enhance successful transplantation of human iPSC-derived insulin-producing cells. Our specific aims in the proposed project are designed to bridge from the completed development of our Mesh Oxygen Transporter into its use in preclinical (animal model) transplantation trials using human iPSC-derived insulin-producing cells. Using small animal models, we will first optimize the dimensions of a refined Mesh Oxygen Transporter that sufficiently supplies oxygen for enhanced graft survival in the SC site, even under conditions of high cell density (more insulin-producing cells in a smaller Mesh). Next, we will load human islets from donors on our Mesh Oxygen Transporter in the SC site in diabetic mice and measure cell function and ability to treat diabetes. Finally, we will load human iPSC-derived insulin-producing cells on our Mesh Oxygen Transporter in the SC site in diabetic mice and measure cell function and ability to treat diabetes. The results we obtain in this project will be promptly translated into large animal preclinical trials and human clinical trials, to directly advance our long-term goal to cure T1D.
Background Rationale
More than one million people in the United States suffer from type 1 diabetes (T1D), which is caused by destruction of the insulin-producing beta cells in the islets of the pancreas. Among current therapeutic options for T1D, insulin therapy (injection of insulin to control blood sugar) is the most common choice for patients. Another promising option includes beta cell replacement therapy, in which doctors place insulin-producing pancreatic islets into the livers of patients. Islet transplantation is advantageous over insulin therapy in maintaining natural blood sugar levels, because of the ability of the transplanted islets to sense blood sugar and adjust it precisely in the patient’s body. Although islets come from donated organs in clinical practice, they are often in short supply. In addition, the environment in the liver, where islets are currently transplanted, lacks oxygen and may kill the transplanted cells; a single patient often requires multiple transplantations, worsening the donor shortage. To address the islet shortage, stem cell-derived insulin-producing cells are rapidly emerging as alternative source for islets. Induced pluripotent stem cells (iPSCs) can be reprogrammed to form other cell types, including insulin-producing cells. Although we have high hopes for using stem cell-derived insulin-producing cells to cure T1D, stem cells have the potential to become cancerous, so it is important to be able to closely monitor or retrieve the transplanted cells if needed. In this regard, the liver is not an appropriate option for stem cell-derived cells; instead, the subcutaneous (SC) tissue under the skin fulfills these requirements. Indeed, the SC site is the only approved site for use of stem cell-derived insulin-producing cells in clinical trials to date. However, the SC site faces a major challenge in achieving an adequate oxygen supply, which hinders transplantation success. Although several research teams have been exploring strategies to provide enough oxygen to cells transplanted in the SC site, a proven method for use in humans has not been established yet. Like other teams, we aim to oxygenate the SC site for improved survival of stem cell-derived insulin-producing cells. However, our oxygenation strategy, a Mesh Oxygen Transporter, is notably distinct from other devices previously developed by other teams. Our approach has the following advantages: 1) our approach is not a bulky “device” but an oxygen-transporting “ultra-thin mesh sheet” (1/40 of 1 millimeter thick) designed to accommodate placement of cells under the skin, which guarantees no patient discomfort; 2) our approach provides a 100%-safe oxygen source from room air, and does not require external oxygen sources; and 3) our Mesh Oxygen Transporter is made with highly “biocompatible” material, which the body will not react to, and which is already used in humans as a pacemaker coating and for other medical devices. Because our project is a multi-institutional collaboration, we are also uniquely positioned to accelerate our approach through early testing and into human use by leveraging our relevant expertise: City of Hope is an active clinical islet transplantation center and a translational T1D research center; California Institute of Technology is a state-of-the-art bioengineering institute; and Kyoto University in Japan is ¬a world-renowned institute for stem cell technology.
Description of Project
Type 1 diabetes (T1D) is characterized by destruction of insulin-producing beta cells in the islets of the pancreas. More than one million people suffer from T1D in the U.S., leaving them at risk for chronically high blood sugar. Treatment for T1D involves injection of insulin, but imprecise dosing often leads to poor blood sugar control and long-term complications. Replacing a patient’s insulin-producing beta cells is a promising alternative approach. This is currently achieved by isolating pancreatic islets from a deceased donor and transplanting them into a patient’s liver. Although islet transplantation significantly improves blood sugar control and reduces complications, few patients with T1D benefit from this therapy, due to a shortage of donors. In addition, it is hard for islets to survive in the liver, causing transplants to fail; for this reason, one patient often requires multiple transplantations, worsening the donor shortage.
Several approaches have the potential to overcome the challenges of a donor shortage and a hostile transplantation site. Producing beta-like, insulin-producing cells in the laboratory, rather than using pancreatic islets from deceased donors, is particularly promising. One Nobel Prize-winning way to achieve this is to use induced pluripotent stem cells (iPSC), adult cells that can be reprogrammed to form other cell types, including insulin-producing cells. The cons of the iPSC approach include a potential for cancer, which requires careful monitoring and easy retrievability after transplantation. In this context, the subcutaneous (SC) tissue under the skin is a promising site for safe transplantation of stem cell-derived insulin-producing cells, because it allows for frequent monitoring. Despite these advantages, a major drawback to SC site transplantation is hypoxia (lack of oxygen), which causes post-transplant cell death. All cells, including donor islets and stem cell-derived insulin-producing cells, require oxygen to live.
Although we know hypoxia is our main challenge, there is no easy solution. Several teams have tried to improve oxygenation for SC-transplanted cells, but there is no clinically established method yet. Obstacles include 1) a bulky implant device unsuitable for human use and 2) a need for concentrated oxygen in the SC site, which may require an oxygen generator or oxygen tank, which in turn raises safety concerns. To overcome these obstacles, we developed a Mesh Oxygen Transporter, which is unique from other devices. First, we do not consider it a “device;” instead, we use an ultra-thin mesh (1/40 of 1 millimeter thick) to sandwich insulin-producing cells in the SC site, which guarantees no patient discomfort. Second, our Mesh Oxygen Transporter shows superior oxygenation because the mesh that holds the islets transports oxygen itself, which enables us to use room air as a self-sustaining oxygen source, rather than a separate oxygen generator.
Our preliminary data show that our Mesh Oxygen Transporter demonstrates excellent function. Our proposed project is intended to move our product from the development stage into clinical application using stem cell-derived insulin-producing cells. As a step toward a preclinical trial, in this project, we expect to show that our Mesh Oxygen Transporter improves transplantation of stem cell-derived insulin-producing cells in the SC site of small animal models. We will accelerate our approach by building on the expertise and resources of a multi-institutional consortium of researchers. City of Hope is an active clinical islet transplantation center and a T1D translational research center. We have been developing SC site islet transplantation strategies in collaboration with researchers using state-of-the-art bioengineering techniques at California Institute of Technology. We will use high-quality, stem cell-derived insulin-producing cells developed by the Center for iPS Cell Research and Application at Kyoto University (Japan), a world-renowned institute led by Dr. Yamanaka, a Nobel Prize awardee for iPSC technology.
Anticipated Outcome
We expect that both donated human pancreatic islets and human induced pluripotent stem cell (iPSC)-derived pancreatic islet cells will efficiently and functionally engraft in the subcutaneous (SC) site using our Mesh Oxygen Transporter. Because our proposed project is intended to fill a gap between the development of the Mesh Oxygen Transporter and preclinical studies in large animals, we will test the ability of our Mesh Oxygen Transporter to improve engraftment in small animal models. We will assess successful engraftment by measuring the secretion of insulin-related hormones from the transplanted cells and observing cure of diabetes in the animal models. In regard to future steps for translation into human use, we are confident that the high oxygenation efficiency of our Mesh Oxygen Transporter, which allows for transplantation of insulin-producing cells in layers, will ensure only a minimal area is needed under the skin. Successful completion of this project will be followed by preclinical large animal testing for scaling-up the approach, followed by human clinical trials using human iPSC-derived pancreatic islet cells.
Relevance to T1D
We aim to establish effective beta cell replacement therapy (transplantation of insulin-producing cells) for patients living with type 1 diabetes (T1D). Current major challenges for beta cell replacement therapy include the non-ideal transplant environment in the conventional liver site, and a shortage of insulin-producing cells from donated pancreases. Our proposed project, an under-the-skin strategy that combines the use of our novel Mesh Oxygen Transporter and induced pluripotent stem cell (iPSC)-derived insulin-producing cells, will have a significant impact on transforming the beta cell replacement strategy for T1D, because it addresses the current needs for an alternative transplantation site and an alternative insulin-producing cell source. This will pave the way for iPSC-derived beta cell replacement therapy in patients with T1D. Our proposed project will have a significant impact on public health by dramatically improving quality of life for tens of millions of adults and children living with T1D worldwide.