Tools and Technologies I
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.
This application focuses on the in vivo evaluation of a retrievable, implantable device for encapsulation and retention of pancreatic progenitors. The applicants have previously demonstrated encapsulation of cells within the device, a semi-permeable pouch-like configuration that can be transplanted into animal models. They have shown that encapsulated pancreatic progenitors can mature and secrete insulin in response to glucose loads, essential features of cells used in treating diabetes. The applicants have also shown that encapsulation of cells in the device can protect the cells from the host immune response. In the first aim, the Principal Investigator (PI) will test transplanted, encapsulated control pancreatic progenitors and hESC-derived pancreatic progenitors for survival, differentiation, and function, including longer-term studies in diabetes models. In the second aim, the composition of cells to be encapsulated will be investigated to ensure optimal maturity and functional relevance. In the third aim, the potential for teratoma formation within the device will be evaluated. Finally, the PI proposes to investigate which transplantation sites would be optimal for subsequent differentiation of encapsulated cells into functional, insulin-secreting derivatives. The reviewers were enthusiastic about the the proposed technology and its potential to advance stem cell science. While technical deficiencies were noted, the overall strength of the research plan and the excellent qualifications of the applicants convinced the reviewers of the proposal’s merits. The reviewers agreed the impact of the proposed technology was potentially huge, given that it could address key roadblocks in translation of stem cell biology. The transplanted cells could provide functional, insulin-producing cells for treating diabetes that are protected from the host’s immune defenses, thereby minimizing or eliminating the need for immune-suppressive treatment. Finally, potential teratomas resulting from undifferentiated hESC could be prevented from invading neighboring tissues due to confinement within the device. In terms of feasibility, the reviewers expressed great confidence in the qualifications of the PI and the research team. The rationale and experimental approach were sound with appropriate description of milestones and timelines. The proposed research was well supported by strong preliminary data, and the PI provided an excellent discussion of potential problems and how these would be addressed. While generally enthusiastic, the reviewers noted several deficiencies that could impact the utility of the proposed technology. Reviewers were uncertain of the limitations of mass exchange through the device and questioned the long-term stability of the device and the potential for cell escape when the capsule breaks down. They raised questions about the growth and long-term survival of transplanted, encapsulated cells and were disappointed that the PI did not propose to investigate these aspects more thoroughly. Finally, there was some uncertainty as to how the comparative studies between the cell populations proposed for encapsulation would be performed and whether variability in the experimental methods would complicate these analyses. In spite of these concerns, the reviewers largely agreed that the proposed experiments would address key needs for bringing new therapies to the clinic. The PI and the proposed collaborators were described as extremely well qualified to perform the described work having been involved in key aspects of the development program to date. One reviewer commented that the team would benefit from additional bioengineering expertise to address potential quantitative issues with mass exchange. Overall, the proposed technology is promising and addresses critical needs in stem cell biology. Despite some weaknesses, the strength of the research team and experimental design were received with enthusiasm.