CRISPR/Cas9 in the Clinic: Xenograft Organ Transplantation

Another endeavor of CRISPR editing application in the clinic occurred on January 7, 2022. On this day, at the University of Maryland Medical Center, an end-stage heart patient underwent transplantation of a CRISPR-edited donor pig heart encompassing a total of 10 edited genes of knocked out and knocked in genes critical for transplantation success.^25,26 The patient's initial response was positive, able to breathe on one’s own. However, eight weeks post-transplantation, the patient suddenly experienced an acute reaction so severe that the patient did not survive the situation. CRISPR technology moved rapidly from the bench to the bedside; there have been great successes, particularly in treating point mutation-associated hereditary disorders, as exemplified by Casgevy.

For more complex medical endeavors such as xenograft heart transplantation, considerable challenges exist, not with CRISPR technology per se, but instead stemming from a multitude of factors, particularly regarding optimal selection of target genes to silence to avoid or minimize organ rejection.

Note: The removal of selected genes is a work in progress in terms of efficacy assessment. More research is required to gauge suitability and effectiveness. Indeed, assessment of the suitability of which gene sets to be removed is an ongoing area of research. There are many levels of complexities involved. For example, the removal of CD47 has been shown to enhance favorable anti-rejection reactions in heart xenotransplantation but deleterious in kidney xenotransplantation.

The following pages present a closer look at which genes were CRISPR-edited in the donor pig’s heart.