Periodic Reporting for period 3 - BIOCAPAN (BIOactive implantable CApsule for PANcreatic islets immunosuppression free therapy)
Reporting period: 2018-06-01 to 2019-09-30
Diabetes is a chronic disease characterized by an increase in glucose in the blood. To compensate, type I diabetes mellitus (T1DM) patients need to take insulin several times a day. Among Type II diabetes mellitus (T2DM) patients, one in six patients eventually needs to take insulin. For these patients (about 80 million worldwide) the disease is ever-present in their daily lives, requiring multiple glycaemia measurements, calculations of carbohydrate intake, and insulin injections. Moreover, despite intensive insulin therapy, microangiopathic complications remain a reality for diabetic patients and a small proportion of patients develop brittle diabetes, a rare form of type I diabetes exposing patients to high glucose variability and severe metabolic events such as hypoglycemic coma or keto-acidosis. The key therapeutic issue in diabetes mellitus type I and II is glycaemic control. Reductions of constant self-control, of insulin self-injections, and of long-term complications would have tremendous benefit for the patient’s quality of life. In this context, islet transplantation represents a hope for millions type I and some of type II diabetic patients offering the perspective of an endogenous regulation of glycemia without insulin injection. Islet transplantation or cell therapy of type I diabetes is a technique now validated for the management of unstable diabetic patients and it exposes patients to a lower morbidity and mortality than the pancreas transplantation. The weakness of this therapy remains the organ source and the requirement for life-long immunosuppression, which is often associated with serious adverse events such as hypertension, increased susceptibility to infections and increased risk of cancer. The extension of cell therapy of type I diabetes to the greatest number of patients with type I diabetes is conditioned by the discontinuation of immunosuppressive therapy. Many projects focus on islet encapsulation, which provides an innovative perspective to avoid immunosuppression during transplantation. The concept of encapsulation involves applying a physical barrier between cells and the immune system. Three types of encapsulation are distinguished: macroencapsulation, which consists in grafting the islands in a macro-chamber, microencapsulation, which consists in isolating each islet within a single capsule and Nanoencapsulation which consist of coating each islet with a nanolayer of biomaterial. These projects represent a real challenge since, for over 30 years, several encapsulated islet approaches have been envisaged without, unfortunately, leading to the development of clinically effective products. Obstacles to overcome are represented to capsules fibrosis and islet necrosis within the capsule. These difficulties are addressed in the BIOCAPAN project.
In BIOCAPAN we aim at developing an innovative treatment, based on the implantation of smartly microencapsulated allogeneic pancreatic islets (cluster of cells secreting insulin) =, which will allow an effective long-lasting blood glucose normalization and stabilization, without the need for immunosuppressive therapy. We have three objectives:
1. Design a complex GMP-grade bioactive microcapsule that will enhance biocompatibility, functionality and survival of transplanted allogeneic islets, in order to reach 2-years of insulin injection free treatment, without the need for immunosuppressive therapy.
2. Establish a method to encapsulate freshly harvested islets quickly, using a GMP-grade platform, to provide standardized and reproducible bioactive microcapsules.
3. Establish an Investigational Medicinal Product Dossier (IMPD) in accordance with the provisions of the Advanced Therapy Medicinal Products (ATMP) Regulation
In BIOCAPAN we aim at developing an innovative treatment, based on the implantation of smartly microencapsulated allogeneic pancreatic islets (cluster of cells secreting insulin) =, which will allow an effective long-lasting blood glucose normalization and stabilization, without the need for immunosuppressive therapy. We have three objectives:
1. Design a complex GMP-grade bioactive microcapsule that will enhance biocompatibility, functionality and survival of transplanted allogeneic islets, in order to reach 2-years of insulin injection free treatment, without the need for immunosuppressive therapy.
2. Establish a method to encapsulate freshly harvested islets quickly, using a GMP-grade platform, to provide standardized and reproducible bioactive microcapsules.
3. Establish an Investigational Medicinal Product Dossier (IMPD) in accordance with the provisions of the Advanced Therapy Medicinal Products (ATMP) Regulation
The BIOCAPAN project started in June 2015 allowing 10 teams from 9 institutions around Europe and US to join their forces to reach these ambitious goals.
The strategy chosen to protect pancreatic islets from immune-rejection is to microencapsulate the pancreatic islets into soft, porous and biocompatible microcapsules. During the 52 months of project, based on a bibliographic study and experimental data in vitro and in vivo, the consortium agreed on the definition of a reference microcapsule and a Bioactive microcapsule. Different biomaterials have been developed to improve pancreatic viability and functionality and to reduce pericapsular fibrosis. The biocompatibility of each new biomaterial developed has been evaluated in vitro along with the functionality (by measuring the insulin secretion of the islets).Based on these experiments, the final bioactive capsule composition was selected. This innovative capsule composition was tested first in vitro. Safety and biocompatibility was confimed. The Bioactive microcapsule was also tested in vivo. Even if further tests are needed to show improved functionality, the Bioactive microcapsules implanted in rodents show good no immune response (no fibrosis) and good stability after several weeks of implantation.
Additionally, to answer the second objective of BIOCAPAN, the whole chain of the process has been assessed. Going from GMP production of biomaterials and cells to the process of microencapsulation. All steps have been depicted and risks analysis performed. A microfluidic cartridge was developed to produce high viscous, monodispersed microcapsules. A GMP like instrument was conceived and optimized to automatically produce aseptic microcapsules. The automatic production of capsules was validated. In parallel, the consortium defined the clinical trials specifications and received scientific advices from the regulatory agencies. The draft of the Investigational Medicinal Product Dossier (IMPD) was completed at the end of the project.
The strategy chosen to protect pancreatic islets from immune-rejection is to microencapsulate the pancreatic islets into soft, porous and biocompatible microcapsules. During the 52 months of project, based on a bibliographic study and experimental data in vitro and in vivo, the consortium agreed on the definition of a reference microcapsule and a Bioactive microcapsule. Different biomaterials have been developed to improve pancreatic viability and functionality and to reduce pericapsular fibrosis. The biocompatibility of each new biomaterial developed has been evaluated in vitro along with the functionality (by measuring the insulin secretion of the islets).Based on these experiments, the final bioactive capsule composition was selected. This innovative capsule composition was tested first in vitro. Safety and biocompatibility was confimed. The Bioactive microcapsule was also tested in vivo. Even if further tests are needed to show improved functionality, the Bioactive microcapsules implanted in rodents show good no immune response (no fibrosis) and good stability after several weeks of implantation.
Additionally, to answer the second objective of BIOCAPAN, the whole chain of the process has been assessed. Going from GMP production of biomaterials and cells to the process of microencapsulation. All steps have been depicted and risks analysis performed. A microfluidic cartridge was developed to produce high viscous, monodispersed microcapsules. A GMP like instrument was conceived and optimized to automatically produce aseptic microcapsules. The automatic production of capsules was validated. In parallel, the consortium defined the clinical trials specifications and received scientific advices from the regulatory agencies. The draft of the Investigational Medicinal Product Dossier (IMPD) was completed at the end of the project.
During the project, the consortium performed in vitro and in vivo validations of different biomaterials aiming at the composition of the bioactive capsule. The results obtained with this innovative capsule composition show promising results in vivo. If the results are confirmed, BIOCAPAN would lead to a therapy option eliminating the need for multiple daily glycaemia measurements and insulin injections for at least two years. At the same time, the natural glycaemic homeostasis supported by the implanted islets, would reduce the prevalence of comorbidities. A successful biotherapy with microencapsulated islets will fulfill the expectations of the patients in terms of quality of life, as well as the requirements of public health in terms of reduced cost in use due to better quality of glucose control, and more efficient control of insulin levels than any other insulin delivery methods.