Xenotransplantation: The Contribution of CRISPR/Cas9 Gene Editing Technology

Purpose of Review This review will highlight how gene editing technology using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) has revolutionized the xenotransplantation field, leading to the first pig-to-human kidney and heart xenotransplants. Recent Findings CRISPR/Cas9 gene editing technology has significantly accelerated the development of multi-gene modified pigs to address the major immunological and physiological incompatibilities between pigs and humans. These gene edits include the knockout (KO) of the three porcine-specific glycan epitopes responsible for hyperacute rejection and human transgene expression targeting the coagulation and complement pathways. CRISPR/Cas9 genetic editing has also addressed a critical concern for the potential for cross-species transmission of porcine endogenous retroviruses (PERVs) by allowing the successful generation of pigs with genomically inactivated PERVs to eliminate the risk of viral transmission. CRISPR/Cas9 multi-gene edited pigs are likely to be used in the first human clinical xenotransplant trials. While genetic modifications will help protect pig xenografts from innate immune responses, genetic engineering alone will not be sufficient to prevent chronic rejection, given the overwhelming number of possible xenoantigens that can trigger adaptive immune responses and antibody-mediated rejection. Additional immunomodulatory strategies, such as targeted immunosuppression or tolerance induction, will be required for long-term survival of porcine xenografts.