Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques

Abstract

The transplantation of pancreatic islet cells could restore glycaemic control in patients with type 1 diabetes. Microspheres for islet encapsulation have enabled long-term glycaemic control in rodent models of diabetes; however, humans transplanted with equivalent microsphere formulations have experienced only transient islet graft function owing to a vigorous foreign-body response (FBR), to pericapsular fibrotic overgrowth (PFO) and, in upright bipedal species, to the sedimentation of the microspheres within the peritoneal cavity. Here, we report the results of the testing in non-human primate (NHP) models of seven alginate formulations that were efficacious in rodents, including three that led to transient islet graft function in clinical trials. All formulations elicited significant FBR and PFO 1 month post implantation; however, three chemically modified, immune-modulating alginate formulations elicited a reduced FBR. In conjunction with a minimally invasive transplantation technique into the bursa omentalis of NHPs, the most promising chemically modified alginate derivative (Z1-Y15) protected viable and glucose-responsive allogeneic islets for 4 months without the need for immunosuppression. Chemically modified alginate formulations may enable the long-term transplantation of islets for the correction of insulin deficiency.

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Fig. 1: Empty alginate spheres used in clinical trials induce FBRs and PFO post implantation in NHPs.
Fig. 2: Transplantation method causes differential spatial distribution of alginate spheres post implantation.
Fig. 3: Z1-Y15 alginate protects viable and glucose-responsive allogeneic islets in NHPs without any immunosuppression.

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Acknowledgements

This work was supported jointly by the Chicago Diabetes Project and the JDRF and the Leona M. and Harry B. Helmsley Charitable Trust (grant number 3-SRA-2014-285-M-R (R.L. and D.G.A.)), the US National Institutes of Health (grant numbers DK091526 (J.O.) EB000244 (R.L.), EB000351 (R.L.), DE013023 (R.L.), CA151884 (R.L.) and UC4DK104218 (D.L.G.)), and through a gift from the Tayebati Family Foundation (D.G.A. and R.L.). This work was also supported by the Slovak Research and Development Agency under contract number APVV-14-858 (I.L.). O.V. was supported by JDRF and Department of Defense Congressionally Directed Medical Research Program (DOD/CDMRP) postdoctoral fellowships (grant numbers 3-2013-178 and W81XWH-13-1-0215, respectively). J.C.D. was supported by a JDRF postdoctoral fellowship (grant number 3-PDF-2015-91-A-N). The authors acknowledge L. Halliday and the veterinary staff at the Biological Resource Laboratories at UIC for their assistance and technical support during the course of the studies. We thank R. Calafiore and G. Basta from the University of Perugia for producing the A-PLO-A spheres under current good manufacturing practice conditions at the University of Illinois at Chicago for the herein described experiments. We thank B. Tuch and his team at the Diabetes Transplant Unit, Prince of Wales Hospital, Sydney, Australia, for the production of the UPMVG-Ba2+ spheres and sharing his experience from the clinical trials in encapsulated islet transplant trials conducted in Sydney, Australia. We thank H. H. Tam for his advice on the statistical analysis of datasets.

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M.A.B., O.V., A.J.V., J.J.M., D.G.A. and J.O. designed the experiments, analysed the data and wrote the manuscript. M.A.B., O.V., A.J.V., J.J.M., M.Q., E.M., M.O., J.C.D., J.M.-E., M.N., A.K., C.-C.Y., Y.X., D.I., S.G., J.L., C.L., A.R.B., K.O., M.C., Y.W. and J.O. performed experiments. J.H.-L., D.L.G., G.C.W., B.L.S., A.M.A.R., I.L. and R.L. provided conceptual advice and technical support. R.L., D.G.A. and J.O. supervised the study. All of the authors discussed the results and assisted in the preparation of the manuscript.

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Correspondence to Daniel G. Anderson or Jose Oberholzer.

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O.V., A.J.V., R.L., D.G.A. and J.O. are founding scientists of Sigilon Therapeutics, a biotech company based in Cambridge, MA, USA, that produces antifibrotic materials for cell-based therapies. J.O. is founder and President of CellTrans, a biotech company based in Chicago, IL, USA, for the transplantation of cell-based therapies.

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Supplementary Video 1

Non-invasive laparoscopic transplantation technique for hydrogel spheres into the bursa omentalis

Supplementary Video 2

Non-invasive laparoscopic retrieval of Z1-Y15 spheres containing allogeneic islets performed 1-month post-transplantation

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Bochenek, M.A., Veiseh, O., Vegas, A.J. et al. Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques. Nat Biomed Eng 2, 810–821 (2018). https://doi.org/10.1038/s41551-018-0275-1

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