Project full title: “Macroencapsulated Porcine Pancreatic Islets to cure Diabetes Mellitus type 1/2”

“HEALTH.2013.0-1 HEALTH.2013.0-1 programme, Boosting the translation of health research projects’ results into innovative applications for health; Boosting the translation of health research projects’ results into innovative applications for health.”

Duration: 2013-2015

fp7The main objective of the project is to undertake specific final steps that will enable successful transplantation of pig insulin-producing cells into human T1DM patients by using alginate macroencapsulation and/or pig transgenesis. AVIDIN will develop the necessary tools (DNA arrays, traditional and digital PCR reagent kits,..) for identifying all the pig pathogens including viruses which will need to be controlled in all studies (in vitro and in vivo) and prior to go for clinical trial.

Xeno-Islets Transplantation for Diabetes
In the context of diabetes, the rationale of the present project is heavily supported by the fact that human islets alginate macroencapsulation has been recently approved for use in T1DM patients and a pilot clinical trial (15 patients) is underway at UCL, in Brussels (after formal approval from EMA and the Belgian Medical Authorities). Indeed, like in previous primate experiments, one patient successfully received in February 2011 a sub-cutaneous macroencapsulated patch containing human allogeneic islets. This patch is composed as follows: (1) a collagenic support which is made of human fascia lata (available in accredited Human Tissue Banks) and approved for human use; (2) human pancreatic islets which are lined up on this support and produced according to GMP standards and (3) finally, this monolayer device is embedded both faces in highly purified and biocompatible alginate which is produced (in GMP conditions) by Novamatrix, FMC Biopolymers (Norway) and approved for human use. Although the first endpoint of this study is “safety”, this T1DM patient could significantly reduce his daily use of exogenous insulin and result in a Glycate Hemoglobin reduction below 6.5%.

Although these prove-of-concept results are overwhelming, a scale-up procedure is not yet designed since the use of pig islets instead of human islets could benefit from final developments which are proposed in the present project.

Long term survival of adult pancreatic porcine islets (APPIs) xenografts under the form of a subcutaneous alginate macroencapsulated patch is routinely achievable in diabetic primates without the use of any immunosuppression. When two successive patches are implanted in the same subcutaneous space, the diabetes control may be obtained for over a year). Although these reproducible pre-clinical results have been the basis for a clinical pilot study with macroencapsulated ALLO-islets, they could also form the basis for a clinical pilot study with pig XENO-islets. Still, additional fine tuning of the procedure could be achieved within the next three years, and thereby considerably increasing the chances of success to create a useful device for humans.

The main objectives of this three-year project will be (1) to evaluate in vitro the effect of GLP1 transgene expression in pig islets after hyperglycaemic challenge; (2) to continue to produce transgenic pigs specifically expressing GLP-1 in pig islets under insulin promoter (Avantea srl), and (3) finally to test these modified pig islets in our well characterized pig-to-diabetic primates model in vivo (Université catholique de Louvain). However, in order to use islets from newborn unmodified or transgenic pigs, the consortium will also set up (4) the pig islets isolation and cell maturation technique for Neonates Pancreatic Pig Cluster cells since neonates pig islets have prolonged survival and would also render possible the use of Designed Pathogen Free (DPF) neonates pigs which will represent a key point to reach clinical studies. Biotalentum Ltd. will be mainly involved in this part of the work which is in vitro purification, maturation of NPCCS. Glasgow Caledonian University has a double role since this partner is a high level specialist in identifying known pig viruses (PERVs etc.) and new viruses. In addition, GCU will have a role in the contact with regulatory affairs. AVIDIN will together with Glasgow Caledonian University develop arrays and a set of molecular testing for ALL pig pathogens (microbes,parasites,mycosis) in order to drive this project to clinical trials guidelines.

Besides using traditional techniques, AVIDIN will aplly digital PCR methods enabling precise and sensitive detection of different pathogens in blood or cells. AVIDIN will develop and apply high-throughput, nanoliter QRT-PCR arrays to simultaneously detect different pathogens from the same sample at high sensitivity.

A three year project will allow the consortium to finalise the requirement for clinical trials, since pre-clinical data have been obtained reproducibly and successfully in this model. This research program has the potential to decrease the lack of human cells supply for transplantation and provide a viable solution for patients who today are not even considered for transplantation.