Periodic Reporting for period 2 - ISLET (Advancing Innovative Stem Cell-based Therapy for Diabetes in Europe)
Reporting period: 2021-09-01 to 2023-02-28
Diabetes is characterized by a high level of blood glucose that can lead to serious health problems. In both type 1 diabetes (T1D) and type 2 diabetes (T2D), this is related to insulin levels, the hormone produced by the pancreas that enables blood sugar to enter cells and be used for energy. However, in T2D, insulin production is insufficient or the insulin produced does not work properly. By contrast, in T1D, the body attacks the cells in the pancreas, and they do not make any insulin. Currently, T1D is treated with lifelong insulin therapy via injections or an insulin pump. The EU-funded ISLET project's innovative program uses stem-cell-based human pancreatic islet cells and develops quality control assays that will lead to the rapid commercialization of a game-changing therapy for T1D.
Objectives
Type 1 diabetes (T1D) is one of the main health challenges, affecting 6 million European citizens. Today, T1D accounts for a severe economic burden on healthcare and the labor force. To bring advanced therapy in type T1D to patients, a scalable source of pancreatic islets for transplantation is needed. The objective of the ISLET project is to build and implement a new and innovative program for the production and marketing of human pluripotent stem cell (hPSC)-derived advanced therapy medicinal products (ATMPs) for the treatment of EU citizens with T1D. To achieve this, ISLET gathers a constellation of experts to establish a transferable GMP-compliant manufacturing program based on improved and standardized protocols for the generation and characterization of future ATMPs. Furthermore, to make a product closer to the "golden standard" human pancreatic islet, ISLET will develop islet-like clusters composed of isolated hPSC-derived alpha and beta-like cells and advanced strategies for safe, up-scaled production and a quantitative go/no-go assessment of therapeutic quality. Specifically, to overcome the lack of robust qualitative and quantitative assays to assess islet function, ISLET will introduce a novel quality control concept for predicting the therapeutic efficacy by quantitative proteomics and lipidomics as part of the ATMP development chain - a concept that will be widely applicable. Additionally, a commercial route for exploiting hESC-derived ATMPs for T1D treatment with the EU will be developed. Finally, a professionally supported dual plan for public engagement in the fields of stem cell therapy and diabetes is rounding up the project.
Objectives
Type 1 diabetes (T1D) is one of the main health challenges, affecting 6 million European citizens. Today, T1D accounts for a severe economic burden on healthcare and the labor force. To bring advanced therapy in type T1D to patients, a scalable source of pancreatic islets for transplantation is needed. The objective of the ISLET project is to build and implement a new and innovative program for the production and marketing of human pluripotent stem cell (hPSC)-derived advanced therapy medicinal products (ATMPs) for the treatment of EU citizens with T1D. To achieve this, ISLET gathers a constellation of experts to establish a transferable GMP-compliant manufacturing program based on improved and standardized protocols for the generation and characterization of future ATMPs. Furthermore, to make a product closer to the "golden standard" human pancreatic islet, ISLET will develop islet-like clusters composed of isolated hPSC-derived alpha and beta-like cells and advanced strategies for safe, up-scaled production and a quantitative go/no-go assessment of therapeutic quality. Specifically, to overcome the lack of robust qualitative and quantitative assays to assess islet function, ISLET will introduce a novel quality control concept for predicting the therapeutic efficacy by quantitative proteomics and lipidomics as part of the ATMP development chain - a concept that will be widely applicable. Additionally, a commercial route for exploiting hESC-derived ATMPs for T1D treatment with the EU will be developed. Finally, a professionally supported dual plan for public engagement in the fields of stem cell therapy and diabetes is rounding up the project.
The ISLET project has now been running for 3 years. During the 2nd reporting period existing collaborations have been strengthened and new collaborations have been initiated. All collaborations are driven by highly motivated students and Postdocs within ISLET. ISLET has made significant progress in the predevelopment and preclinical testing of the 1st generation product, determined the final composition and administration route of the 1st generation product in future clinical trials in T1D patients, and resolved scientific and methodological questions relevant to the 2nd generation product. Some of this work has been published. A robust scalable GMP-compliant protocol for functional H9-derived beta cells was established. The safety and functionality of H9-derived beta cells were tested by transplanting them under the kidney capsule of STZ-diabetic mice. The grafted cells gradually developed glucose-responsiveness and restored normoglycemia in a dose-dependent manner. Towards generation of a 2nd generation cell product, which more closely mimics the human islet, discoveries were made on the mechanisms of progenitor expansion and endocrinogenesis. Furthermore, reconstructing islet like clusters demonstrated that alpha cells are necessary for proper insulin secretion. An innovative goal of ISLET is to develop a method for predicting the therapeutic capacity of a cell product. Towards this goal proteomics was used to define the maturation process of beta cells. Preliminary data show that the cellular lipidome gives an insight into the metabolic cell health and thus has the potential to provide a quantitative readout for cell health. Therefore, the combination of proteomics and lipidomics would provide information on whether the quality of the cell preparation to be transplanted is suitable for transplantation or not. Finally, management and coordinator tasks have been successfully transferred from UCPH to HMGU.
Expected impact 1: Identification of potential regenerative therapies to address unmet clinical needs of large patient groups.
T1D has an enormous negative impact on daily life and therefore creates a large disease burden. Thus, ISLET will establish a programme with the long-term goal of implementing continuous improvement of ATMPs.
The proof of feasibility to generate functional beta cells from hPSCs in pre-clinical diabetic animal models has indicated we are ready to move towards the mass production of beta cells for large groups of patients. To this end, ISLET will establish a transferable platform to implement a pipeline for the activity described above.
Expected impact 2: Strengthening of Europe's position in translational regenerative medicine. ATMP development activities are primarily centred in the USA and driven by large pharma and biotech companies. However, in the diabetes field, where there is a massive market for currently available treatment options, new ATMP-based approaches offer a less initial financial incentive for pharmaceutical companies.
ISLET will establish itself as a role model for collaboration and coordination of the whole value chain by bringing together basic and clinical research within the regulatory and legal landscape for hPSC-based ATMP development and commercialisation. Thus, ISLET will ensure that new ATMPs for the treatment of T1D meet the requirements for a commercially viable product that will ultimately reach the market.
Expected impact 3: New therapies for major human diseases and conditions and new approaches for therapy taken further in the development pipeline.
In general, stem cell researchers in many disease areas struggle with generating fully mature and therapeutically active stem cell-derived cell types. Another technological bottleneck is the scalability of research differentiation protocols under GMP-compliant conditions.
The consortium is based on expertise and a scalable manufacturing strategy with a unique expansion/differentiation/cell purification concept. The hESC-based medicinal product will be manufactured in full compliance with regulatory requirements for clinical use. In addition, the consortium will complement traditional in vitro and in vivo assays for quality control by developing new beyond-state-of-the-art predictive measures using proteomic and lipidomic profiling. Therefore, providing a novel quantitative readout more potent than existing methods for assessing manufacturing quality.
T1D has an enormous negative impact on daily life and therefore creates a large disease burden. Thus, ISLET will establish a programme with the long-term goal of implementing continuous improvement of ATMPs.
The proof of feasibility to generate functional beta cells from hPSCs in pre-clinical diabetic animal models has indicated we are ready to move towards the mass production of beta cells for large groups of patients. To this end, ISLET will establish a transferable platform to implement a pipeline for the activity described above.
Expected impact 2: Strengthening of Europe's position in translational regenerative medicine. ATMP development activities are primarily centred in the USA and driven by large pharma and biotech companies. However, in the diabetes field, where there is a massive market for currently available treatment options, new ATMP-based approaches offer a less initial financial incentive for pharmaceutical companies.
ISLET will establish itself as a role model for collaboration and coordination of the whole value chain by bringing together basic and clinical research within the regulatory and legal landscape for hPSC-based ATMP development and commercialisation. Thus, ISLET will ensure that new ATMPs for the treatment of T1D meet the requirements for a commercially viable product that will ultimately reach the market.
Expected impact 3: New therapies for major human diseases and conditions and new approaches for therapy taken further in the development pipeline.
In general, stem cell researchers in many disease areas struggle with generating fully mature and therapeutically active stem cell-derived cell types. Another technological bottleneck is the scalability of research differentiation protocols under GMP-compliant conditions.
The consortium is based on expertise and a scalable manufacturing strategy with a unique expansion/differentiation/cell purification concept. The hESC-based medicinal product will be manufactured in full compliance with regulatory requirements for clinical use. In addition, the consortium will complement traditional in vitro and in vivo assays for quality control by developing new beyond-state-of-the-art predictive measures using proteomic and lipidomic profiling. Therefore, providing a novel quantitative readout more potent than existing methods for assessing manufacturing quality.