First Full Reversal of Diabetes in Non-human Primates (nhp) with Stem Cell Derived Islet-like-clusters (sc-ilcs)

J. Lei¹, S. Collins², H. Deng¹, Z. Yang¹, A. Zhang¹, C. Peters¹, J. Zhang², K. Boulanger², M. Yu³, M. Rickels³, C. Liu³, R. Pop², A. Naji³, D. Melton², J. Markmann¹

¹Surgery, Mass General, Boston, MA, ²Harvard Stem Cell Institute, Harvard University, Boston, MA, ³Surgery, Upenn, Philadelphia, PA

Meeting: 2021 American Transplant Congress

Abstract number: LB 27

Keywords: Biopsy, Graft acceptance, Primates, Stem cells

Topic: Basic Science » Cellular Therapies, Tissue Engineering/Regenerative Medicine

Session Information

Session Name: Cellular Therapies, Tissue Engineering/Regenerative Medicine

Session Type: Poster Abstract

Session Date & Time: None. Available on demand.

Location: Virtual

*Purpose: Deceased donor allo-islet transplants (Tx) have demonstrated the ability of cell-based therapy to fully reverse T1D, however, an inadequate donor supply and frequent need for islets from multiple donors compromises utility. SC-ILCs may provide a limitless cell source to treat T1D. We examined the ability of SC- ILCs to gain full glycemic control in 2 diabetic NHP.

*Methods: Cyno macaques (C1 and C2) were rendered diabetic with Streptozotocin (75gm/kg) and maintained on insulin for >1 mo prior to Tx. Absence of endogenous c-peptide by IVGTT was documented pretransplant. Stage 6 ILCs were prepared from HUES8 ES cells by the Melton lab, as previously described. C1 and C2 (5.4 and 4.0 Kg) received ILCs (200K and 160K ILC particles; 96K and 104K IEq/kg; packed cell volume 2.0 and 1.8ml, respectively). One-third of ILCs were injected into the liver via the PV and 2/3 into the omental bursa. 2X/day glucose monitoring, periodic IVGTT, and glucose potentiated arginine testing was performed. Immunosuppression (IS) to prevent xenograft rejection included Pre-Tx anti-CD20 and rATG, and anti-CD40L and belatacept maintenance.

*Results: C1 and C2 promptly gained normoglycemia off insulin. C1 developed a disseminated CMV infection and was sacrificed at d24. Histology of C1 at sacrifice and biopsy of C2 at d120 demonstrated healthy islets in liver and omentum. C2 was normoglycemic off-insulin for >6 mo. IS was then weaned to assess whether rejection would eliminate the graft; ILC function gradually deteriorated thereafter. Serial BGs and IVGTT of C2 pre and post-Tx is shown(fig1). Prolonged fasting did not induce severe hypoglycemia suggesting effective counter regulation.

*Conclusions: Stem cell derived ILCs achieved robust regulation of glycemia in diabetic NHP as indicated by daily glucoses, IVGTT, robust glucose potentiated arginine stimulation and absence of dysregulated insulin secretion with fasting. These results portend fine glycemic control in human recipients of stem cell derived islets.

To cite this abstract in AMA style:

Lei J, Collins S, Deng H, Yang Z, Zhang A, Peters C, Zhang J, Boulanger K, Yu M, Rickels M, Liu C, Pop R, Naji A, Melton D, Markmann J. First Full Reversal of Diabetes in Non-human Primates (nhp) with Stem Cell Derived Islet-like-clusters (sc-ilcs) [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/first-full-reversal-of-diabetes-in-non-human-primates-nhp-with-stem-cell-derived-islet-like-clusters-sc-ilcs/. Accessed November 21, 2024.

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