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Genetically engineered pig heart transplantation in non-human primates

2025; Nature Portfolio; Volume: 5; Issue: 1 Linguagem: Inglês

10.1038/s43856-025-00731-y

2730-664X

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

Virus-based gene therapy research

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. 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. 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). 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. There is a shortage of organs donated for use in transplantation. Instead, animal organs could potentially be used for people with end-stage organ failure. We modified pig hearts to make them more like human organs and transplanted them into non-human primates. The pig hearts functioned in the non-human primates for up to 225 days. These hearts could also potentially be used in people with heart failure. Singh, Goerlich et al. transplant 10 gene modified pig hearts into non-human primates. Life-supporting function occurred for up to 225 days but there was evidence of adipose deposition, chronic vasculopathy, micro and macro thrombosis, and acute cellular rejection.