Development of the Theracyte Cellular Encapsulation System for Delivery of human ES Cell-derived Pancreatic Islets and Progenitors.
Tools and Technologies I
Statement of Benefit to California:
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.