Progressive genetic modifications of porcine cardiac xenografts extend survival to 9 months
Muhammad M. Mohiuddin, Corbin E. Goerlich, Avneesh K. Singh, Tianshu Zhang, Ivan Tatarov, Billeta Lewis, Faith Sentz, Alena Hershfeld, Gheorghe Braileanu, Patrick Odonkor, Erik Strauss, Brittney Williams, Allen Burke, Jamie Hittman, Adnan Bhutta, Ali Tabatabai, Anuj Gupta, Todd Vaught, Lori Sorrells, Kasinath Kuravi, Amy Dandro, Will Eyestone, David Kaczorowski, David Ayares, Bartley P. Griffith
Abstract
We report orthotopic (life-supporting) survival of genetically engineered porcine cardiac xenografts (with six gene modifications) for almost 9 months in baboon recipients. This work builds on our previously reported heterotopic cardiac xenograft (three gene modifications) survival up to 945 days with an anti-CD40 monoclonal antibody-based immunosuppression. In this current study, life-supporting xenografts containing multiple human complement regulatory, thromboregulatory, and anti-inflammatory proteins, in addition to growth hormone receptor knockout (KO) and carbohydrate antigen KOs, were transplanted in the baboons. Selective "multi-gene" xenografts demonstrate survival greater than 8 months without the requirement of adjunctive medications and without evidence of abnormal xenograft thickness or rejection. These data demonstrate that selective "multi-gene" modifications improve cardiac xenograft survival significantly and may be foundational for paving the way to bridge transplantation in humans.