Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques
Xiaomeng Hu, Kathy White, Ari G. Olroyd, Rowena DeJesus, Antonia A. Dominguez, William E. Dowdle, Annabelle M. Friera, Chi Young, Frank Wells, Elaine Y. Chu, Cade Ellis Ito, Harini Krishnapura, Surbhi Jain, Ramya Ankala, Trevor J. McGill, August Lin, Kyla Egenberger, Allison Gagnon, J. Michael Rukstalis, Nathaniel J. Hogrebe, Corie Gattis, Ron Basco, Jeffrey R. Millman, Paul Kievit, Mark M. Davis, Lewis L. Lanier, Andrew J. Connolly, T. Deuse, Sonja Schrepfer
Abstract
Abstract Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient’s immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 ( B2M −/− CIITA −/− CD47 + ). To determine whether this strategy is successful in non-human primates, we engineered rhesus macaque HIP cells and transplanted them intramuscularly into four allogeneic rhesus macaques. The HIP cells survived unrestricted for 16 weeks in fully immunocompetent allogeneic recipients and differentiated into several lineages, whereas allogeneic wild-type cells were vigorously rejected. We also differentiated human HIP cells into endocrinologically active pancreatic islet cells and showed that they survived in immunocompetent, allogeneic diabetic humanized mice for 4 weeks and ameliorated diabetes. HIP-edited primary rhesus macaque islets survived for 40 weeks in an allogeneic rhesus macaque recipient without immunosuppression, whereas unedited islets were quickly rejected.