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Background <p>Improvement in gene modifications of donor pigs has led to the prevention of early cardiac xenograft rejection and significantly prolonged cardiac xenograft survival in both heterotopic and orthotopic preclinical non-human primate (NHP) models. This progress formed the basis for FDA approval for compassionate use transplants in two patients.</p> Methods <p>Based on our earlier report of 9-month survival of seven gene-edited (7-GE) hearts transplanted (life-supporting orthotopic) in baboons, we transplanted 10 gene-edited pig hearts into baboons (<i>n</i> = 4) using non-ischemic continuous perfusion preservation (NICP) and immunosuppression regimen based on co-stimulation blockade by anti-CD40 monoclonal antibody. This pivotal study expands on the 7-GE backbone, with 3 additional gene edits, using 10-GE pigs as donors to baboon recipients.</p> Results <p>10 GE cardiac xenografts provide life-supporting function up to 225 days (mean 128 ± 36 days) in a non-human primate model. Undetectable or latent porcine cytomegalovirus (PCMV) does not influence cardiac xenograft survival in this study but still needs more exploration with a larger cohort. Xenograft histology demonstrates adipose (Fat) deposition (<i>n</i> = 1), chronic vasculopathy (<i>n</i> = 1), micro and macro thrombosis, and acute cellular rejection (<i>n</i> = 1).</p> Conclusions <p>These data demonstrate that 10 GE cardiac xenografts have variable cardiac xenograft survival in NHP due to perhaps presence of 4th antigen and require further study. However, these 10GE organs may be suitable for clinical cardiac xenotransplantation and have already been utilized in two human cases.</p>

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Genetically engineered pig heart transplantation in non-human primates

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月7日

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  • Avneesh K. Singh,
  • Corbin E. Goerlich,
  • Tianshu Zhang,
  • Billeta Lewis,
  • Alena Hershfeld,
  • Gheorghe Braileanu,
  • Kasinath Kurvi,
  • Kathryn Rice,
  • Faith Sentz,
  • Sarah Mudd,
  • Patrick Odonkor,
  • Erik Strauss,
  • Brittney Williams,
  • Allen Burke,
  • Anuj Gupta,
  • Cinthia B. Drachenberg,
  • David Ayares,
  • Bartley P. Griffith,
  • Muhammad M. Mohiuddin

摘要

Background

Improvement in gene modifications of donor pigs has led to the prevention of early cardiac xenograft rejection and significantly prolonged cardiac xenograft survival in both heterotopic and orthotopic preclinical non-human primate (NHP) models. This progress formed the basis for FDA approval for compassionate use transplants in two patients.

Methods

Based on our earlier report of 9-month survival of seven gene-edited (7-GE) hearts transplanted (life-supporting orthotopic) in baboons, we transplanted 10 gene-edited pig hearts into baboons (n = 4) using non-ischemic continuous perfusion preservation (NICP) and immunosuppression regimen based on co-stimulation blockade by anti-CD40 monoclonal antibody. This pivotal study expands on the 7-GE backbone, with 3 additional gene edits, using 10-GE pigs as donors to baboon recipients.

Results

10 GE cardiac xenografts provide life-supporting function up to 225 days (mean 128 ± 36 days) in a non-human primate model. Undetectable or latent porcine cytomegalovirus (PCMV) does not influence cardiac xenograft survival in this study but still needs more exploration with a larger cohort. Xenograft histology demonstrates adipose (Fat) deposition (n = 1), chronic vasculopathy (n = 1), micro and macro thrombosis, and acute cellular rejection (n = 1).

Conclusions

These data demonstrate that 10 GE cardiac xenografts have variable cardiac xenograft survival in NHP due to perhaps presence of 4th antigen and require further study. However, these 10GE organs may be suitable for clinical cardiac xenotransplantation and have already been utilized in two human cases.