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

Antonio Bruni; Andrew R. Pepper; Rena L. Pawlick; Boris Gala-Lopez; Anissa Gamble; Tatsuya Kin; Andrew J. Malcolm; Carissa Jones; Jon D. Piganelli; James D. Crapo; A. M.James Shapiro

doi:10.1111/ajt.14705

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

Antonio Bruni, Andrew R. Pepper, Rena L. Pawlick, Boris Gala-Lopez, Anissa Gamble, Tatsuya Kin, Andrew J. Malcolm, Carissa Jones, Jon D. Piganelli, James D. Crapo, A. M.James Shapiro

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1879-1889
Number of pages	11
Journal	American Journal of Transplantation
Volume	18
Issue number	8
DOIs	https://doi.org/10.1111/ajt.14705
Publication status	Published - Aug 2018
Externally published	Yes

Bibliographical note

Funding Information:
Diabetes Research Foundation (5-2013-91, 47-2013-517, and 2-SRA-2014-296-Q-R). Dr. James D. Crapo is supported by BioMimetix JV, LLC, by NCI HHSN 261201500002C and NIH 1R4CA195749 to BioMimetix JV, LLC and by NIH R01 HL089897 to National Jewish Health

Funding Information:
Dr. A.M James Shapiro is supported through a Senior Clinical Scholarship from Alberta Innovates Health Solutions (AIHS) and holds a Canada Research Chair in Transplantation Surgery and Regenerative Medicine funded through the government of Canada. A.M.J.S is also supported by AIHS CRIO Team Award #201201154, the Diabetes Research Institute Foundation Canada (DRIFCan) and the Canadian National Transplant Research Program. Antonio Bruni is supported by a grant from Stem Cell Network (NCESCN CTRA FY17/CT5). Dr. Andrew R. Pepper is supported primarily through an AIHS PostDoctoral Fellowship. Dr. Boris Gala-Lopez is supported through an AIHS Clinician Fellowship. Anissa Gamble is supported by a studentship through the Alberta Diabetes Institute. Dr. Jon D. Piganelli is supported by the American Diabetes Association (CDA 7.07, CD-16, and 1-12-BS-161) and Juvenile

Publisher Copyright:
© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons

ASJC Scopus Subject Areas

Immunology and Allergy
Transplantation
Pharmacology (medical)

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/ajt.14705

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Bruni, A., Pepper, A. R., Pawlick, R. L., Gala-Lopez, B., Gamble, A., Kin, T., Malcolm, A. J., Jones, C., Piganelli, J. D., Crapo, J. D., & Shapiro, A. M. J. (2018). BMX-001, a novel redox-active metalloporphyrin, improves islet function and engraftment in a murine transplant model. American Journal of Transplantation, 18(8), 1879-1889. https://doi.org/10.1111/ajt.14705

@article{eaab214dd33f40eba78565f135581075,

title = "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 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.",

author = "Antonio Bruni and Pepper, {Andrew R.} and Pawlick, {Rena L.} and Boris Gala-Lopez and Anissa Gamble and Tatsuya Kin and Malcolm, {Andrew J.} and Carissa Jones and Piganelli, {Jon D.} and Crapo, {James D.} and Shapiro, {A. M.James}",

note = "Funding Information: Diabetes Research Foundation (5-2013-91, 47-2013-517, and 2-SRA-2014-296-Q-R). Dr. James D. Crapo is supported by BioMimetix JV, LLC, by NCI HHSN 261201500002C and NIH 1R4CA195749 to BioMimetix JV, LLC and by NIH R01 HL089897 to National Jewish Health Funding Information: Dr. A.M James Shapiro is supported through a Senior Clinical Scholarship from Alberta Innovates Health Solutions (AIHS) and holds a Canada Research Chair in Transplantation Surgery and Regenerative Medicine funded through the government of Canada. A.M.J.S is also supported by AIHS CRIO Team Award #201201154, the Diabetes Research Institute Foundation Canada (DRIFCan) and the Canadian National Transplant Research Program. Antonio Bruni is supported by a grant from Stem Cell Network (NCESCN CTRA FY17/CT5). Dr. Andrew R. Pepper is supported primarily through an AIHS PostDoctoral Fellowship. Dr. Boris Gala-Lopez is supported through an AIHS Clinician Fellowship. Anissa Gamble is supported by a studentship through the Alberta Diabetes Institute. Dr. Jon D. Piganelli is supported by the American Diabetes Association (CDA 7.07, CD-16, and 1-12-BS-161) and Juvenile Publisher Copyright: {\textcopyright} 2018 The American Society of Transplantation and the American Society of Transplant Surgeons",

year = "2018",

month = aug,

doi = "10.1111/ajt.14705",

language = "English",

volume = "18",

pages = "1879--1889",

journal = "American Journal of Transplantation",

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TY - JOUR

T1 - BMX-001, a novel redox-active metalloporphyrin, improves islet function and engraftment in a murine transplant model

AU - Bruni, Antonio

AU - Pepper, Andrew R.

AU - Pawlick, Rena L.

AU - Gala-Lopez, Boris

AU - Gamble, Anissa

AU - Kin, Tatsuya

AU - Malcolm, Andrew J.

AU - Jones, Carissa

AU - Piganelli, Jon D.

AU - Crapo, James D.

AU - Shapiro, A. M.James

N1 - Funding Information: Diabetes Research Foundation (5-2013-91, 47-2013-517, and 2-SRA-2014-296-Q-R). Dr. James D. Crapo is supported by BioMimetix JV, LLC, by NCI HHSN 261201500002C and NIH 1R4CA195749 to BioMimetix JV, LLC and by NIH R01 HL089897 to National Jewish Health Funding Information: Dr. A.M James Shapiro is supported through a Senior Clinical Scholarship from Alberta Innovates Health Solutions (AIHS) and holds a Canada Research Chair in Transplantation Surgery and Regenerative Medicine funded through the government of Canada. A.M.J.S is also supported by AIHS CRIO Team Award #201201154, the Diabetes Research Institute Foundation Canada (DRIFCan) and the Canadian National Transplant Research Program. Antonio Bruni is supported by a grant from Stem Cell Network (NCESCN CTRA FY17/CT5). Dr. Andrew R. Pepper is supported primarily through an AIHS PostDoctoral Fellowship. Dr. Boris Gala-Lopez is supported through an AIHS Clinician Fellowship. Anissa Gamble is supported by a studentship through the Alberta Diabetes Institute. Dr. Jon D. Piganelli is supported by the American Diabetes Association (CDA 7.07, CD-16, and 1-12-BS-161) and Juvenile Publisher Copyright: © 2018 The American Society of Transplantation and the American Society of Transplant Surgeons

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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