Periodic Reporting for period 3 - ISLET (Advancing Innovative Stem Cell-based Therapy for Diabetes in Europe)
Berichtszeitraum: 2023-03-01 bis 2024-02-29
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
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
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 four years. During the RP3 existing collaborations have been strengthened and new collaborations have been initiated. 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 significant progress in developing a scalable GMP-manufacturing platform to produce H9-derived β cells for preclinical safety and efficacy studies starting in 2024. To achieve this goal, a strategy that involves generating and characterizing cell banks, as well as developing a new GMP-compliant differentiation protocol was established. Previous transplantation experiments raised safety concerns due to cyst formation observed on the grafts. To address this potential safety issue, two modified versions of the differentiation protocol (GII and Gseci) were simultaneously developed and tested in kidney transplantations, confirming that cysts no longer formed with the GII protocol. To further increase the safety and effectiveness of the final product, a dissociation/reaggregation step was added. This step is crucial as it helps remove off-target and dead cells from the GII protocol, thereby enhancing the purity and quality of the final product. Also, discoveries in the molecular mechanisms of expanding multipotent progenitors (MPP) and differentiating them into β cells. They have also identified new potential targets to induce endocrine specification. These discoveries provide new translatable knowledge that can be used to improve the scalability and differentiation efficiency of the 2nd generation product. Reconstructing islet like clusters (chimeric islets) containing specific amounts of α and δ cells in combination with β cells was used to define which cell interactions β cells function relies on. The analysis of the proteome of various batches of SC-islets in order to identify signatures that can be used for quality control, to assess the therapeutic capacity of the ISLET product. This data should also facilitate defining which part of the mature proteome corresponds to the maturation process. Furthermore, ISLET continue to partner with Eurostemcell and EuroGCT, and as at the outset, our strategy is to invest in dissemination.
A significant progress in developing a scalable GMP-manufacturing platform to produce H9-derived β cells for preclinical safety and efficacy studies starting in 2024. To achieve this goal, a strategy that involves generating and characterizing cell banks, as well as developing a new GMP-compliant differentiation protocol was established. Previous transplantation experiments raised safety concerns due to cyst formation observed on the grafts. To address this potential safety issue, two modified versions of the differentiation protocol (GII and Gseci) were simultaneously developed and tested in kidney transplantations, confirming that cysts no longer formed with the GII protocol. To further increase the safety and effectiveness of the final product, a dissociation/reaggregation step was added. This step is crucial as it helps remove off-target and dead cells from the GII protocol, thereby enhancing the purity and quality of the final product. Also, discoveries in the molecular mechanisms of expanding multipotent progenitors (MPP) and differentiating them into β cells. They have also identified new potential targets to induce endocrine specification. These discoveries provide new translatable knowledge that can be used to improve the scalability and differentiation efficiency of the 2nd generation product. Reconstructing islet like clusters (chimeric islets) containing specific amounts of α and δ cells in combination with β cells was used to define which cell interactions β cells function relies on. The analysis of the proteome of various batches of SC-islets in order to identify signatures that can be used for quality control, to assess the therapeutic capacity of the ISLET product. This data should also facilitate defining which part of the mature proteome corresponds to the maturation process. Furthermore, ISLET continue to partner with Eurostemcell and EuroGCT, and as at the outset, our strategy is to invest in dissemination.
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.