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Tailored Elastin-like Recombinamers as Advanced Systems for Cell Therapies in Diabetes Mellitus: a Synthetic Biology Approach towards a Bioeffective and Immunoisolated Biosimilar Islet/Cell Niche

Periodic Reporting for period 3 - ELASTISLET (Tailored Elastin-like Recombinamers as Advanced Systems for Cell Therapies in Diabetes Mellitus: a Synthetic Biology Approach towards a Bioeffective and Immunoisolated Biosimilar Islet/Cell Niche)

Reporting period: 2018-06-01 to 2019-05-31

ELASTISLET is within the context of DM, a global epidemic that comprises a series of clinically and genetically heterogeneous physiological disorders. According to the first WHO Global report on diabetes demonstrates that the number of adults living with diabetes has almost quadrupled since 1980 to 422 million.
Most current therapies for DM have been developed in the absence of defined molecular targets and of a full understanding of the disease pathogenesis. In the most severe cases insulin therapy is indeed and, to date, any treatment has not a been able to imitate its regulated secretion. Because of its chronic nature and the severity of the associated complications, DM is extremely costly, both for the affected individuals and for the health authorities. Moreover, we have to considerate the aggravating factor of its alarming increasing rate. This highlights the substantial financial burden that nowadays DM imposes on society.
Recently, important progresses have been made in clinical islet transplantation nevertheless they are mainly limited by the adverse effects of the immunosuppressive therapy and the limited availability of donor tissue. An important decay of the graft function usually occurs in transplanted patients within 1-5 years post-transplant. ELASTISLET strategy aim at making cell therapy a real and effective treatment for DM by thoroughly addressing some critical points that seriously affects patients´ quality of life and that has not been overcome so far. The general objective of ELASTISLET is the development of a novel and breakthrough immunoisolation and scaffolding systems based on multibiofunctional elastin-like recombinamers (ELRs) for long-term and efficient pancreatic islet and human induced pluripotential stem cells (hiPSCs) transplantation for Diabetes Mellitus (DM) treatment. This objective is materialized in the fabrication of multibiofunctional capsules able to efficienciently inmmunoisolate their content and to get completely biointegrated in the host surrounding tissues (Figs 1, 2)
Along the 3rd period, the number of ELR versions has substantially increased at the request of the consortium with the aim of enhancing the capsules performance in both strategies. At month 48, there were 40 ELR available versions fully characterized and purified. Indeed, they have been up-scaled in GMP-like conditions, with a purity higher than 98% and high stability level upon storage.
Since the beginning of the project, Strategy A (conformational capsules via click chemistry reaction of complementary ELRs) resulted in a higher rate of successful encapsulation regading Strategy B (superficial modification of the cells).
The consortium has delivered a prototype of an automated encapsulation system that pretends an up-scaled gentle and efficient covering of the cells without damaging the biological material nor compromising its viability.
As for regulatory issues, the ITF meeting concluded that the ELRs should be considered medical devices as they are a part of the final product and represent a material intended to be used in human beings for modifiying a physiological process (immune response and diffusion of nutrients). This classification was reinforced by the EMA´s Committee of Advanced Therapies (CAT), which concluded that ELR encapsulated human pancreatic islets were not an ATMP.
The in vitro assays and in vivo transplantations confirmed the efficiency of the Strategy A encapsulating approach both for islets and hiPSC spehoids. The proof of concept of the immunoprotective effect was demonstrated for both types of cells without any detrimental effects on glucose induced insulin secretion and engraftment after in vivo transplantation
The ELRs by themselves demonstrated to be immunologically inert according to different in vivo and in vitro immune approaches. The lack of immune rejection and robust insulin production enabled physiologically functional vascularization surrounding the coated islets even without the presence of angiogenic peptide (QK) in the outer surface of the capsule. However, the ability of ELRs containing QK to further improve the vascularization around the implanted islets was also demonstrated.
Along the last period, some specific initiatives were undertaken to disseminate the project outcomes. Strong emphasis were made in the final dissemination and networking symposium at TERMIS EU 2019. A realistic exploitation plan has been delivered in month 48. It outlines a viable strategy for the protection and commercialization of the exploitable results by means of the creation of a start-up company named “PanCoat”. A patentability study confirming that the procedure for cells encapsulation (Strategy A) is new and inventive has been delivery and a draft of the relevant patent is ongoing
Exogenous subcutaneous insulin delivery is imprecise, and even optimized subcutaneous pumps and sensors fail to provide physiologic insulin delivery with sufficiently dynamic insulin release or shut-off. For this reason the use of biological cell-based approaches, such as Elastislet, are preferred for sustained precision normoglycaemia.
Clinical pancreatic islet transplantation is one of the safest and least invasive transplant procedures that holds great promise for the treatment of DM. Currently, this therapy has two important drawbacks that Elastislet has successfully overcome.
The first one is that the availability of pancreas from deceased donors is quite limited and can restrict the applicability of the islets transplantation procedure. Elastislet has set up a protocol for the differentiation of hiPSC that leads to pancreatic endocrine cell phenotypes that permit to obtain unlimited and cost-effective sources of insulin-producing cells and other endocrine cell clusters.
The second one is the necessity for immuno-suppressive drugs post-transplant, which may lead to important complications such as infection, cancer and organ system toxicity. It has been demonstrated that ELRs, being fully immunologically inert and biocompatible, can effectively coat the cells and prevent immune rejection in different in vivo models. The proof of concept for immunoprotection of allogeneic islets and hiPSCs in experimental transplantation has been stablished.
Since the encapsulated islets and hiPSCs have demonstrated to be absolutely ignored by the immune system, the persistence and functionality of the implant are quite longer than in current transplantation strategies in which the cells are not coated or the capsule is not fully immune-protective.
According to the literature, the current clinic results of non-coated islets transplantation give evidence of a prevalence of insulin independence of approximately one year in immune-suppressive patients. It is expected that Elastislet prevalence will be higher without the need for immune-suppressants, thanks to the effective immune-protection effect of the capsule, which will have a high impact in patient’s quality of life.
The elimination of immunosuppressant drugs in transplanted patients not only reduces the prevalence of associated complications but also the need for recurrent transplants. All of this results in an important reduction of the post-transplant medical costs with regard to the current transplantation strategies, which is estimated to be around the 43% of the total costs associated to DM.
Therefore, Elastislet has taken an important step toward the definitive cure of DM
Figure 1: Encapsulation estrategy based on elastin-based bioinpired materials
Figure 2: Semi-permeable nature and adecuate selectivity of the elastin-based encapsulating material
Figure 3: Intact human islets with preserved cellular composition 4 wks after implantation to immuno