BMX-001, a novel redox-active metalloporphyrin, improves islet function and engraftment in a murine transplant model

  • Am J Transplant. 2018 Aug;18(8):1879-1889. doi: 10.1111/ajt.14705.
Antonio Bruni  1  2  3 ,  Andrew R Pepper  1  2  3 ,  Rena L Pawlick  1 ,  Boris Gala-Lopez  1  2  3 ,  Anissa Gamble  1  2 ,  Tatsuya Kin  1 ,  Andrew J Malcolm  1  3 ,  Carissa Jones  4 ,  Jon D Piganelli  5  4 ,  James D Crapo  6  4 ,  A M James Shapiro  1  2  3
Affiliations
  • 1. Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
  • 2. Department of Surgery, University of Alberta, Edmonton, AB, Canada.
  • 3. Canadian National Transplant Research Program, Edmonton, AB, Canada.
  • 4. BioMimetix JV, LLC, Englewood, CO, USA.
  • 5. Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • 6. Department of Medicine, National Jewish Health, Denver, CO, USA.
PMID: 29464912 DOI: 10.1111/ajt.14705
Abstract

Islet transplantation has become a well-established therapy for select patients with type 1 diabetes. Viability and engraftment can be compromised by the generation of oxidative stress encountered during isolation and culture. We evaluated whether the administration of BMX-001 (MnTnBuOE-2-PyP5+ [Mn(III) meso-tetrakis-(N-b-butoxyethylpyridinium-2-yl)porphyrin]) and its earlier derivative, BMX-010 (MnTE-2-PyP [Mn(III) meso-tetrakis-(N-methylpyridinium-2-yl)porphyrin]) could improve islet function and engraftment outcomes. Long-term culture of human islets with BMX-001, but not BMX-010, exhibited preserved in vitro viability. Murine islets isolated and cultured for 24 hours with 34 μmol/L BMX-001 exhibited improved Insulin secretion (n = 3 isolations, P < .05) in response to glucose relative to control islets. In addition, 34 μmol/L BMX-001-supplemented murine islets exhibited significantly reduced Apoptosis as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling, compared with nontreated control islets (P < .05). Murine syngeneic islets transplanted under the kidney capsule at a marginal dose of 150 islets revealed 58% of 34 μmol/L BMX-001-treated islet recipients became euglycemic (n = 11 of 19) compared with 19% of nontreated control islet recipients (n = 3 of 19, P < .05). Of murine recipients receiving a marginal dose of human islets cultured with 34 μmol/L BMX-001, 92% (n = 12 of 13) achieved euglycemia compared with 57% of control recipients (n = 8 of 14, P = .11). These results demonstrate that the administration of BMX-001 enhances in vitro viability and augments murine marginal islet mass engraftment.

Keywords
diabetes; islet transplantation; islets of Langerhans; translational research/science.
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