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

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 24hours with 34μmol/L BMX-001 exhibited improved insulin secretion (n=3 isolations, P<.05) in response to glucose relative to control islets. In addition, 34μmol/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 34μmol/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 34μmol/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.