Diabetes

Coding Dimension ID: 
289
Coding Dimension path name: 
Diabetes

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.

Endodermal differentiation of human ES cells

Funding Type: 
SEED Grant
Grant Number: 
RS1-00308
ICOC Funds Committed: 
$635 242
Disease Focus: 
Diabetes
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
The goals of this proposal are to investigate endodermal differentiation and proliferation in human ES cell cultures. Endodermal cells give rise to the epithelial lining of the respiratory and digestive tract as well as to the liver and pancreas. The future treatment of diseases such as type I diabetes using stem cell therapy relies on our ability to differentiate stem cells into endoderm, a prerequisite step to forming pancreatic beta cells. In 2005, D’Amour et al. reported the efficient differentiation of human ES cells into endoderm. This report provides a potentially effective protocol that needs to be further evaluated (specific aim 1). In addition, given that the success of stem-cell therapy depends on our ability to generate large numbers of differentiated cells (e.g. 200-700 million beta cells per patient are currently being used in the Edmonton protocol), we will investigate the ability of the endodermal generated in specific aim 1 cells to proliferate in culture (specific aim 2).
Statement of Benefit to California: 
Stem cell therapy relies on the development of efficient and reproducible protocols to differentiate stem cells into various cell types such as pancreatic beta cells. The first step to making pancreatic beta cells is the differentiation of stem cells into so-called endodermal cells, one of the 3 basic cell types of the body. In addition, in order to make stem cell therapy a viable option, one needs to be able to generate large numbers of differentiated cells from stem cells. Our proposal aims to establish such protocols. The health of California and its citizens will ultimately benefit from this research as it will help develop stem cell therapies.
Progress Report: 
  • The goals of this proposal are to investigate endodermal differentiation and proliferation of human ES cells in culture. Endodermal differentiation is a necessary step towards making pancreatic beta cells, as well as other endodermal cells such as liver cells. Pancreatic beta cells generated from human ES cells could be used to treat type I diabetics. In the past two years, we have incorporated human ES cell culture technology into our laboratory and have been able to replicate data obtained by other research groups. While several other research groups and companies around the world are focused on making pancreatic beta cells as quickly as possible, we strongly believe that a more detailed understanding of the biology of human ES cell differentiation into endoderm will help the optimization of this protocol. Therefore, we have focused our efforts on testing a number of variables in the initial step of creating definitive endoderm. We have found that different human ES cell lines have very different capacity to differentiate into endoderm under the same culture conditions. In addition, we have recently focused our research effort on the post-translational modifications of key regulators of endoderm differentiation, and found a critical role for a poorly appreciated modification, namely a sugar modification called GlcNAcylation. In summary, developing a reproducible and efficient way to differentiate human ES cells into endoderm, as well as a thorough understanding of this key step, will allow us and others to elucidate the detailed set of molecular and biochemical events underlying this critical differentiation step, and will improve differentiation protocols.
  • The goals of this proposal are to investigate endodermal differentiation and proliferation of human ES cells in culture. Endodermal differentiation is a necessary step towards making pancreatic beta cells, as well as other endodermal cells, such as liver cells. Pancreatic beta cells generated from human ES cells could be used to treat type I diabetes. In the past two years, we have incorporated human ES cell culture technology into our laboratory and have been able to replicate data obtained by other research groups. While several other research groups and companies around the world are focused on making pancreatic beta cells as quickly as possible, we strongly believe that a more detailed understanding of the biology of human eS cell differentiation into endoderm will help the optimization of this protocol. Therefore, we have focused our efforts on testing a number of variables in the initial step of creating definitive endoderm. We have found that different human ES cell lines have very different capacity to differentiate into endoderm under the same culture conditions. IN addition, we have recently focused our research effort on the post-translational modifications of key regulators of endoderm differentiation, and found a critical role for a poorly appreciated modification—namely a sugar modification called GlcNAcylation. In summary, developing a reproducible and efficient way to differentiate human ES cells into endoderm, as well as thorough understanding of this key step, will allow us and others to elucidate the detailed set of molecular and biochemical events underlying this critical differentiation step, and will improve differentiation protocols.
  • We initiated a project on the role of post-translational modifications during hES cell differentiation into endodermal lineages, specifically on the GlcNAcylation sugar modification. We found that this modification appears to be important for endoderm formation in hES cell cultures. Identification of modified proteins is an important next step in understanding the mechanisms of this phenomenon and may ultimately provide a basis to develop assays for screening drugs that enhance endoderm/beta-cell formation.

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