Extended Survival of 9- and 10-Gene-Edited Pig Heart Xenografts with Ischemia Minimization and CD154 Costimulation Blockade-Based Immunosuppression.

Xenotransplantation costimulation pathway blockade genetic engineering heart transplantation swine

Journal

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
ISSN: 1557-3117
Titre abrégé: J Heart Lung Transplant
Pays: United States
ID NLM: 9102703

Informations de publication

Date de publication:
01 Aug 2024
Historique:
received: 19 04 2024
revised: 18 06 2024
accepted: 26 07 2024
medline: 4 8 2024
pubmed: 4 8 2024
entrez: 3 8 2024
Statut: aheadofprint

Résumé

Xenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, either alone or with addition of various human complement, coagulation, and anti-inflammatory 'transgenes'. Here we evaluated results associated with gene-edited (GE) pig hearts transplanted in baboons using an established costimulation-based immunosuppressive regimen and a cold-perfused graft preservation technique. Eight baboons received heterotopic abdominal heart transplants from 3-GE (GalKO.β4GalNT2KO.hCD55, n=3), 9-GE (GalKO.β4GalNT2KO.GHRKO.hCD46.hCD55. TBM.EPCR.hCD47.HO-1, n=3) or 10-G (9-GE+CMAHKO, n=2) pigs using Steen's cold continuous perfusion for ischemia minimization. Immunosuppression (IS) included induction with anti-thymocyte globulin and αCD20, ongoing αCD154, MMF, and tapered corticosteroid. All three 3-GE grafts functioned well initially, but failed within 5 days. One 9-GE graft was lost intraoperatively due to a technical issue and another was lost at POD 13 due to antibody mediated rejection (AMR) in a baboon with a strongly positive pre-operative cross-match. One 10-GE heart failed at POD113 with combined cellular and antibody mediated rejection. One 9-GE and one 10-GE hearts had preserved graft function with normal myocardium on protocol biopsies, but exhibited slowly progressive graft hypertrophy until elective necropsy at POD393 and 243 respectively. Elevated levels of IL-6, MCP-1, C-reactive protein, and human thrombomodulin were variably associated with conditioning, the transplant procedure, and clinically significant postoperative events. Relative to reference genetics without thrombo-regulatory and anti-inflammatory gene expression, 9- or 10-GE pig hearts exhibit promising performance in the context of a clinically applicable regimen including ischemia minimization and αCD154-based IS, justifying further evaluation in an orthotopic model.

Sections du résumé

BACKGROUND BACKGROUND
Xenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, either alone or with addition of various human complement, coagulation, and anti-inflammatory 'transgenes'. Here we evaluated results associated with gene-edited (GE) pig hearts transplanted in baboons using an established costimulation-based immunosuppressive regimen and a cold-perfused graft preservation technique.
METHODS METHODS
Eight baboons received heterotopic abdominal heart transplants from 3-GE (GalKO.β4GalNT2KO.hCD55, n=3), 9-GE (GalKO.β4GalNT2KO.GHRKO.hCD46.hCD55. TBM.EPCR.hCD47.HO-1, n=3) or 10-G (9-GE+CMAHKO, n=2) pigs using Steen's cold continuous perfusion for ischemia minimization. Immunosuppression (IS) included induction with anti-thymocyte globulin and αCD20, ongoing αCD154, MMF, and tapered corticosteroid.
RESULTS RESULTS
All three 3-GE grafts functioned well initially, but failed within 5 days. One 9-GE graft was lost intraoperatively due to a technical issue and another was lost at POD 13 due to antibody mediated rejection (AMR) in a baboon with a strongly positive pre-operative cross-match. One 10-GE heart failed at POD113 with combined cellular and antibody mediated rejection. One 9-GE and one 10-GE hearts had preserved graft function with normal myocardium on protocol biopsies, but exhibited slowly progressive graft hypertrophy until elective necropsy at POD393 and 243 respectively. Elevated levels of IL-6, MCP-1, C-reactive protein, and human thrombomodulin were variably associated with conditioning, the transplant procedure, and clinically significant postoperative events.
CONCLUSION CONCLUSIONS
Relative to reference genetics without thrombo-regulatory and anti-inflammatory gene expression, 9- or 10-GE pig hearts exhibit promising performance in the context of a clinically applicable regimen including ischemia minimization and αCD154-based IS, justifying further evaluation in an orthotopic model.

Identifiants

DOI: 10.1016/j.healun.2024.07.022 PMID: 39097214
pubmed: 39097214
pii: S1053-2498(24)01777-7
doi: 10.1016/j.healun.2024.07.022
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Auteurs

Ryan Chaban (R)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Cardiovascular Surgery, University Hospital of Mainz, Mainz, Germany.

Ikechukwu Ileka (I)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Gannon McGrath (G)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Kohei Kinoshita (K)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Zahra Habibabady (Z)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Madelyn Ma (M)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Victoria Diaz (V)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Akihiro Maenaka (A)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Anthony Calhoun (A)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Megan Dufault (M)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Ivy Rosales (I)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Christiana M Laguerre (CM)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Seyed-Amir Sanatkar (SA)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Lars Burdorf (L)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Revivicor, Inc., Blacksburg, VA, USA.

David L Ayares (DL)

Revivicor, Inc., Blacksburg, VA, USA.

William Eyestone (W)

Revivicor, Inc., Blacksburg, VA, USA.

Prachi Sardana (P)

Revivicor, Inc., Blacksburg, VA, USA.

Kasinath Kuravi (K)

Revivicor, Inc., Blacksburg, VA, USA.

Lori Sorrells (L)

Revivicor, Inc., Blacksburg, VA, USA.

Seth Lederman (S)

Tonix Pharma LLC, Chatham, NJ, USA.

Caroline G Lucas (CG)

National Swine Resource and Research Center (NSRRC), Columbia, MO, USA.

Randall S Prather (RS)

National Swine Resource and Research Center (NSRRC), Columbia, MO, USA.

Kevin D Wells (KD)

National Swine Resource and Research Center (NSRRC), Columbia, MO, USA.

Kristin M Whitworth (KM)

National Swine Resource and Research Center (NSRRC), Columbia, MO, USA.

David Kc Cooper (DK)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Richard N Pierson Iii (RN)

Center for Transplantation Sciences and Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: rpierson@mgh.harvard.edu.

Classifications MeSH