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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - BetaCellTherapy (Beta Cell Generation by Stem Cell-Derived Implants in Diabetes)

Teaser

Summary

Despite improved treatment, diabetes remains a chronic disease with major health risks and heavy burden on patients and society. Serious forms are caused by depletion in pancreatic beta cells and subsequent loss of glucose control through regulated insulin release. Their cure requires replacement by a metabolically adequate beta cell mass. Islet cell grafts prepared from human donor pancreases can correct a diabetic state in patients but their shortage indicates the need for large-scale sources of therapeutic cells as might be generated by human stem cells. The objective of this project is to identify conditions under which a functional beta cell mass can be established in device-encapsulated human embryonic stem cell (hu-ES)-derived implants subcutaneously placed in diabetes patients. Data from preclinical models guide pilot studies in patients with different (auto)immune status. State-of-the art methods and markers investigate the biology of implants and monitor host immune and innate reactivity. Formation and maturation of stem cell generated beta cells are assessed through comparison with human pancreatic beta cells in currently used clinical grafts. Influences of neighboring cells and microenvironment are examined in order to define and improve conditions that help achieve a functional beta cell mass. Preclinical studies with grafts prepared from human induced pluripotent stem cell (hu-iPS) compare influences of their initial composition and differentiation stage and examine outcome when derived from diabetes patients. Pilot data will determine transition to subsequent levels in clinical protocols, or indicate needs for further laboratory development. The combined clinical and preclinical studies are also expected to contribute knowledge to the physio(patho)logy of human beta cells in an ectopic micro-organ and its use for developing beta cell replacement therapies.

Work performed

The work addresses four specific aims. It achieved the following results:

1. Production of quality controlled human cell preparations:

1) human donor pancreatic islet cells: GMP-operational for (pre)clinical studies
2) hu-ES-derived cells and devices: GMP-operational for (pre)clinical studies
3) hu-iPS-derived cells and devices: operational for preclinical studies

2. Clinical study on human stem cell-generated implants in diabetes patients

1) List of candidate patients established
2) Clinical trial application submitted to Regulatory Authority
3) Reference studies on human donor pancreatic islet cell implants in confined site

3. Preclinical studies for further development of human stem cell-generated implants

1) Validated mouse model for assessing formation and maturation of functional beta cell mass in hu-ES and hu-iPS-generated implants and comparing graft and implant conditions for efficacy and reproducibility
2) Correlation between in vivo and ex vivo markers of functional beta cell mass
3) Biologic characteristics of hu-ES- generated implants achieving metabolic control
4) In vivo conditions improving outcome of implants: ongoing

4. Biomarkers of implant biology and recipient reactivity

1) Readiness of state-of-the art markers for use in preclinical and clinical studies
Discovery of novel markers for prediction outcome and for monitoring autoreactivity
2) Absence of circulating signs of allo- and autoreactivity in diabetes recipients of device-encapsulated hu-ES-PE-implant
3) In vitro platform showing hypo-immunogenicity of hu-ES-PE cells and allosensitization by their endocrine differentiated derivative

Final results

This project is expected to progress beyond the current state-of-the art in beta cell replacement therapy for diabetes patients. It aims identification of conditions under which human stem cell derived implants can generate physiologically regulated beta cells when placed under the skin of patients. This achievement provides important support and useful guidance to the development of human stem cells as a large-scale source for therapeutic cells. It can thus meet a priority in diabetes research and contribute to novel cell therapy protocols that correct the diabetic state in patients with beta cell depletion. This outcome has a major positive impact on the life of these patients; it also suppresses the burden of the disease on society.

Progress of this project should however be considered as one step in a long-term effort towards clinical success and implementation. Translating laboratory findings to clinical studies is indeed an essential component but is also expected to raise new questions and issues to be addressed. Our consortium provides the expertise to drive preclinical and clinical studies over obstacles towards the objectives. It is also expected to generate new knowledge of relevance to beta cell therapy in general.