Periodic Reporting for period 5 - BetaCellTherapy (Beta Cell Generation by Stem Cell-Derived Implants in Diabetes)
Reporting period: 2021-06-01 to 2022-08-31
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 variable quality and organ shortage indicates the need for large-scale sources of therapeutic cells as might be generated by human stem cells. The objective of this project was to identify conditions under which a functional beta cell mass can be established in device-encapsulated human pluripotent stem cell (hu-PSC)-derived implants in type 1 diabetes patients.
Studies in preclinical models served to identify components in grafts and in environment of implants that influence outcome. State-of-the art methods were used to investigate the biology of implants and assess their functional effect. The formation and maturation of the beta cell mass was followed in time and compared with characteristics of human donor pancreatic beta cells in clinical grafts. Markers for monitoring host immune and innate reactivity to the implants were defined. In the perspective of autografts, a preclinical study line with hu-PSC-derived cells produced from type 1 diabetes patients was included.
The preclinical studies guided phase 1 and phase 2 clinical trials with device-encapsulated hu-PSC-derived pancreatic endoderm that was placed in the subcutis of patients. This translational project led to the first report in literature on a beneficial effect of a stem cell product in type 1 diabetic patients, and thus provided proof-of-principle for its therapeutic potential. In vivo data on metabolic outcome were correlated with in situ analysis of retrieved implants. The combination of clinical and preclinical data indicated causes for failure and targets for improvement. It also contributed knowledge to the physio(patho)logy of human beta cells in an ectopic micro-organ and its use for developing beta cell replacement therapies.
Studies in preclinical models served to identify components in grafts and in environment of implants that influence outcome. State-of-the art methods were used to investigate the biology of implants and assess their functional effect. The formation and maturation of the beta cell mass was followed in time and compared with characteristics of human donor pancreatic beta cells in clinical grafts. Markers for monitoring host immune and innate reactivity to the implants were defined. In the perspective of autografts, a preclinical study line with hu-PSC-derived cells produced from type 1 diabetes patients was included.
The preclinical studies guided phase 1 and phase 2 clinical trials with device-encapsulated hu-PSC-derived pancreatic endoderm that was placed in the subcutis of patients. This translational project led to the first report in literature on a beneficial effect of a stem cell product in type 1 diabetic patients, and thus provided proof-of-principle for its therapeutic potential. In vivo data on metabolic outcome were correlated with in situ analysis of retrieved implants. The combination of clinical and preclinical data indicated causes for failure and targets for improvement. It also contributed knowledge to the physio(patho)logy of human beta cells in an ectopic micro-organ and its use for developing beta cell replacement therapies.
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
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
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.
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.