Diabetes

Coding Dimension ID: 
289
Coding Dimension path name: 
Diabetes

Generation of a functional thymus to induce immune tolerance to stem cell derivatives

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07262
ICOC Funds Committed: 
$1 191 000
Disease Focus: 
Immune Disease
HIV/AIDS
Diabetes
Stem Cell Use: 
Embryonic Stem Cell
Cell Line Generation: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Stem cell research offers the promise of replacing missing or damaged tissues in the treatment of disease. Stem-cell-derived transplants still face problems with rejection as in traditional organ transplants. Several drugs can prevent rejection but also suppress the immune system, leaving patients vulnerable to infections and cancer. To avoid rejection without using drugs requires re-educating the immune system to “tolerate” the transplant and not see it as foreign. Because of its role in educating developing immune cells, the thymus is a critical organ in establishing what the immune system recognizes as “self” and not foreign, in a process known as immune tolerance. By growing a new thymus from stem cells matched to transplanted tissues, we can condition the immune system to be tolerant to the transplant and avoid chronic immunosuppression. We have developed a method to grow stem cells into thymic cells that become normal thymus tissue when grafted into mouse models. Notably, the new thymus can promote normal development of immune cells, indicating the potential for generating new, tolerant immune cells. We propose to induce immune tolerance to other stem-cell derived tissues using stem-cell-derived thymus tissue to engineer tolerance. We will optimize our methods of growing thymus tissue, which will be used to condition mice to accept stem-cell-derived pancreas grafts, testing their ability both to prevent rejection and to cure diabetes in a transplant model.
Statement of Benefit to California: 
The proposed work aims to improve the effectiveness of stem cell treatments by preventing immunological rejection of transplanted tissue derived from stem cells. An important barrier to the clinical use of stem-cell-derived organs and tissues is the potential of the immune system to reject or damage this regenerated tissue. Improved approaches to address immune rejection are needed since stem cell therapies are underway in treating diseases that have a wide impact on the health of Californians, including diabetes, Parkinson’s disease, Alzheimer’s disease, retinal eye diseases, and musculoskeletal diseases. The proposed studies will improve treatment for these diseases by providing a novel method to halt immunologic rejection or destruction of tissues that are derived from stem cells. We have successfully developed methods to grow thymus tissue, which controls the ability of the immune system to be “tolerant” of transplanted tissue. Here we will improve methods to generate thymus from stem cells and show that it can promote survival of transplanted tissue derived from the same cells. By using the thymus to condition the immune system towards tolerance, we hope to avoid immune rejection without the use of immunosuppressive drugs. Induction of a tolerant immune system in this way would represent a significant advance in improving stem cell therapies. Thus, this work could have a broad impact on a large number of the disease treatments that involve stem cells.

Preclinical and clinical testing of a stem cell-based combination product for insulin-dependent diabetes

Funding Type: 
Strategic Partnership I
Grant Number: 
SP1-06513
Investigator: 
ICOC Funds Committed: 
$10 075 070
Disease Focus: 
Diabetes
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Diabetes exacts a tremendous toll on patients, their families, and society. Autoimmune Type 1 diabetes, often called juvenile-onset diabetes, is caused by a person’s own immune system mistakenly destroying their insulin-producing cells in the pancreas, known as beta cells. When those beta cells are lost, the ability to produce insulin in response to consumed carbohydrates is lost, and blood sugar can increase to toxic levels. Although not due to autoimmunity, Type 2 diabetics often lose their ability to produce insulin as well. While pharmaceutical insulin is commonly used to control both types of diabetes, it is difficult to self-administer optimally, does not sufficiently replace beta cells, and the adverse short- and long-term effects of diabetes and risks associated with insulin usage remain, including potentially fatal hypoglycemic episodes, nerve damage, blindness, kidney failure, foot ulcers / amputations, and heart disease. Ideally, one would like to replace lost beta cells, and attempts to do so have included the use of pancreas transplants, beta cell (islet) transplants, and transplants of animal cells. Unfortunately, those approaches are hindered by 1) a limited amount of donor tissue, and 2) issues regarding immunological incompatibility between donors and recipients. To solve the first problem, the group applying for this CIRM award has developed methods to make replacement beta cells from human embryonic stem cells (hESC), which can be reliably grown in large-scale batches. The hESC-derived beta cells have been shown to cure experimental diabetes in mice and rats. Regarding the issue of donor-recipient compatibility, the group has found that the cells can be administered under the skin in a simple device, essentially an envelope made of semi-permeable membrane, which is intended to protect the implanted cells from the patient’s immune system. Upon implant, the cell-loaded device, which also keeps the implanted cells in place, acquires its own dedicated circulation. This blood supply provides oxygen and nutrients to the implanted cells, and also allows them to respond to blood sugar by releasing pancreatic hormones such as insulin into the circulation. Thus, the implanted cell-loaded device in essence represents a “replacement endocrine pancreas” with its own protection from autoimmunity. This product could return a patient's blood sugar regulation to normal and alleviate both the day-to-day and long-term issues of diabetes. The group has made tremendous progress in moving the product from concept through years of research and development. At this point an array of detailed work on the exact format to be tested in humans needs to be completed and submitted to the FDA on the way to clinical trials. The proposed award would provide critical funding, including potentially triggering matching funding from a large corporate partner, to advance the product through the first-in-human testing which will be very informative.
Statement of Benefit to California: 
Diabetes mellitus currently afflicts approximately 350 million people worldwide, with projections of over 500 million by the year 2030 (sources: World Health Organization; International Diabetes Federation). In the year 2000 there were an estimated 2,089,657 cases of diabetes in California (diagnosed + undiagnosed; source: Diabetes Control Program, California Department of Health Services). Further, the disease disproportionately affects certain minority groups and the elderly. Despite the use of insulin and advances in its delivery, the human cost of diabetes is underscored by the financial costs to society: tens of billions of dollars each year in California alone. The primary cause of Type 1 diabetes, and contributing significantly to Type 2 diabetes as well, is the loss of insulin-producing pancreatic beta cells. The proposed Partnership will develop a beta cell replacement therapy for insulin-dependent diabetes. If successful, the therapy will go beyond insulin function, and will perform the full array of normal beta cell functions, including responding in a more physiological manner than manual or mechanized insulin administration. Because they will be more physiological, the replacement cells should also reduce the long-term effects of diabetes. Moreover, the cell therapy will alleviate patients of the constant monitoring of blood glucose and painful insulin injections. For these reasons, it is possible that the product could transform the diabetes treatment landscape dramatically and even replace pharmaceutical insulin in the market. This product will be available in California first, through clinical testing, and if approved by the FDA for commercial production, will eventually help hundreds of thousands of Californians with diabetes. The product will substantially increase quality of life for patients and their families while significantly reducing the health care burden in the state. The proposed Partnership will employ Californian doctors and scientists, and success will generate accolades and notoriety for the state. Lastly, once commercially marketed, the product will yield additional jobs in manufacturing, sales, and related industries, and generate revenue for California. Given the market need and the clear feasibility, the product could become the most significant stem cell-based medical treatment of the coming decade, and that will be a great achievement for California, its taxpayers, and CIRM.

Engineered matrices for control of lineage commitment in human pancreatic stem cells

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07398
ICOC Funds Committed: 
$526 896
Disease Focus: 
Diabetes
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 
Patients with end-stage type 1 diabetes (T1D) can be effectively managed by allogeneic islet transplantation. However, a severe cadaveric organ shortage greatly limits use of this promising procedure. Stem cells have the potential to provide a solution to this bottleneck because of their ability to self-renew and differentiate into islet β-cells. Although progress has been made in coaxing human embryonic stem (ES) cells to differentiate into pancreatic progenitor-like cells in culture, there are safety concerns regarding ES cell-derived products because of their ability to form teratomas in vivo. In contrast, adult tissue cells lack teratoma potential. Our goal is to develop, for transplantation, insulin-expressing cells derived from adult human pancreatic progenitor-like cells. If successful, the proposed research will establish a new paradigm for the development of cell products derived from adult pancreata and enable important advances in cell replacement therapy for T1D. This research will allow human cadaveric adult pancreatic tissues, which are largely discarded after islet isolation, to be used to maximum efficiency in transplantation. Moreover, the results of these studies will be applicable to the treatment of end-stage type 2 diabetes patients, in whom islet β-cells are exhausted and dysfunctional.
Statement of Benefit to California: 
In type 1 and some type 2 diabetic patients, the pancreatic β-cells, which secrete insulin in response to elevated glucose concentrations in the blood, are insufficient or dysfunctional. Insulin injection is the most common form of therapy to control diabetes. However, insulin injection cannot match the physiological response conferred by endogenous β-cells, and complications inevitably develop over time. Allogeneic islet transplantation is beneficial to those diabetic patients who have developed end-stage complications. However, it is estimated that fewer than 1% of Californians most in need of islet transplantation can benefit from the procedure because there is a severe shortage of human cadaveric pancreas organs. This dire situation has led to the search for alternative sources of β-cells for transplantation. If human adult pancreatic stem and progenitor cells can be coaxed to differentiate into β-like cells in culture, they would provide large numbers of cells for replacement therapy. This proposal addresses the important challenge of producing β-cells through differentiation of human pancreatic stem and progenitor cells, with the ultimate objective of developing new treatments for diabetic patients.

Development of the Theracyte Cellular Encapsulation System for Delivery of human ES Cell-derived Pancreatic Islets and Progenitors.

Funding Type: 
Tools and Technologies I
Grant Number: 
RT1-01093
Investigator: 
ICOC Funds Committed: 
$827 072
Disease Focus: 
Diabetes
Stem Cell Use: 
Adult Stem Cell
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
There are several challenges to the successful implementation of a cellular therapy for insulin dependent diabetes derived from Human Embryonic Stem Cells (hESCs). Among these are the development of functional insulin-producing cells, a clinical delivery method that eliminates the need for chronic immunosuppression, and assurance that hESC-derived tumors do not develop in the patient. We have recently developed methods to efficiently generate such insulin-producing cells from Human Embryonic Stem Cells that can prevent diabetes in mouse models of the disease. The results demonstrated for the first time that Human Embryonic Stem Cells could indeed serve as a source of cellular therapy for diabetes. However, the clinical use of Human Embryonic Stem Cell-derived cell products is hampered by safety concerns over the potential growth of unwanted cell types and the formation of tumors. Encapsulation of cellular transplants has the potential to reduce or eliminate the need for immunosuppression. Moreover, a durable immunoprotective device which prevented cell escape could serve as a platform for safely administering Human Embryonic Stem Cell-derived therapies. The [REDACTED] device, a planar polytetrafluorethylene (PTFE) pouch-like encapsulation device, features 100% encapsulation and is fully retrievable. We and others have demonstrated in various animal models that the device provides obust protection of transplanted cells against immune attack from the host, [REDACTED] -encapsulated insulin-producing cells can correct diabetes in animals, and the device can prevent the escape and spread of cancer cells. Therefore, the goal of the proposed studies is to evaluate the retrievable [REDACTED] cell encapsulation device in combination with Human Embryonic Stem Cell-derived pancreatic progenitor cells for the treatment of diabetes in mice.
Statement of Benefit to California: 
With a current prevalence of greater than 170 million individuals world-wide, diabetes has attained epidemic proportions. The widespread secondary complications of kidney failure, cardiovascular disease, peripheral nerve disease, and severe retinopathies, this disease extracts a relentless and costly toll on the patients and the health care establishments required for their treatment. Current estimates are that California spends minimally $12 billion on diabetes not including lost wages. There are more than 300,000 diabetes related hospitalizations costing $3.4 billion annually. To date, cellular replacement has been performed either by transplantation of whole pancreas organs, or via infusion of isolated primary pancreatic islets into the portal vein . While effective, the availability of such procedures is severely limited for the treatment of the general diabetes population since it relies upon the extremely limited supply of pancreas organs from deceased donors and usually requires life-long administration of immuno-suppressive drugs. Recent advances in human embryonic stem cell research indicate that the production of a virtually unlimited supply of functional insulin-producing cells is possible. However, much research is required to determine how to safely administer such cells as a therapy because they could give rise to tumors. The animal studies proposed in this application address this with a device that could both protect the therapeutic cells from host immune attack, and protect the host from tumor formation. If successful, our research would provide a possible opportunity for safely administering a diabetes therapy derived from human embryonic stem cells.
Progress Report: 
  • Currently, the shortage of donor organ tissue and risks associated with lifelong immunosuppression limit islet transplantation to only the most severely impacted brittle patients with diabetes. Thus, successful development of a universal cell therapy to treat diabetes requires a renewable safe source of glucose responsive human islet cells and a means for their delivery without the use of chronic immunosuppression. While human embryonic stem cells (hESCs) represent an excellent starting material for the generation of numerous islet cells, the clinical use of hESC-derived cell products is hampered by safety concerns over the potential growth of unwanted cell types and the formation of teratomas. A cell delivery system that allows for both segregation of the hESC-derived graft from host tissues and complete retrieval of the engrafted cells would provide an additional level of safety for hESC-derived cell therapies. The rationale behind this proposal, therefore, is to evaluate an immunoisolation device in combination with hESC-derived pancreatic progenitors as a means for the widespread treatment of diabetes without immunosuppression.
  • Immunoisolation involves the encapsulation of therapeutic graft cells in a membrane (essentially a sealed pouch) thereby protecting the graft from direct contact with the host immune cells and potentially reducing and/or eliminating the need for chronic co-administration of potent anti-rejection drugs for the life of the graft. The encapsulating membrane physically separates the graft cells from host tissues and vasculature. Therefore, to maintain viability and functional metabolism of the graft, the membrane must permit adequate diffusion of oxygen, nutrients, and waste-products, while also preventing exposure to host immune cells. Finally, an encapsulating membrane ideally allows for the timely delivery of insulin at levels that maintain safe and stable blood sugar levels.
  • Our hESC-derived pancreatic progenitor cells are first implanted and the cells complete their maturation to fully functional glucose-responsive islet cells several weeks after engraftment into a host animal. One of the notable achievements over the past year has been the demonstration that the encapsulation device can not only sustain the viability of the pancreatic progenitor cells, but also supports the maturation of those cells to fully functional glucose responsive endocrine tissue. We also have demonstrated that encapsulated grafts prevent the development of diabetes in animals that are treated with a toxin that selectively kills their endogenous pancreatic insulin producing beta cells. The encapsulated grafts maintained normal blood sugar levels in these animals, essentially functioning in place of their beta cells. Finally, all of the encapsulated grafts were fully contained in the interior of the device and there were no breached or ruptured devices observed, even when highly proliferative cells were encapsulated in the device. These results suggest that such an encapsulation device may be a viable system to safely deliver an hESC-derived cell therapy for diabetes.
  • During the second year of our grant we have determined two important features:
  • 1- The encapsulation device we assessed here allows for the efficient development of functional insulin-producing grafts derived from differentiated human embryonic stem cells. We show that in the vast majority of implanted mice (93%) robust insulin-production was detected. Moreover, supporting their potential therapeutic value, in 19 of 19 animals that were challenged with the chemical destruction of their own insulin-producing cells the encapsulated grafts prevented the onset of diabetes.
  • 2- We have used an imaging technology and genetically modified human embryonic stem cells to assess the grafts of differentiated embryonic stem cells in animals as the functional insulin delivery capacity develops over time. These studies showed that the encapsulation device fully contains the grafts: no hESC-derived cells were found outside of the implanted encapsulation device. This supports the premise that the device can be used to safely administer a population of cells derived from hESC.

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