Genetically engineered pig heart transplantation in non-human primates

Area of Science:

• Xenotransplantation research
• Gene editing in animal models
• Cardiovascular surgery

Background:

• Advancements in gene-edited donor pigs have reduced early cardiac xenograft rejection and improved survival in non-human primate models.
• These improvements paved the way for FDA approval of compassionate use cardiac xenotransplantation in two patients.

Purpose of the Study:

• To evaluate the efficacy of 10 gene-edited (10-GE) pig hearts in baboon recipients.
• To assess long-term cardiac xenograft survival and function using a novel preservation and immunosuppression strategy.

Main Methods:

• Transplantation of 10-GE pig hearts into baboons (n=4) using life-supporting orthotopic transplantation.
• Utilized non-ischemic continuous perfusion preservation (NICP) and a co-stimulation blockade immunosuppression regimen (anti-CD40 mAb).
• Expanded upon a previous 7-GE model with three additional gene edits.

Main Results:

• 10-GE cardiac xenografts provided life-supporting function for up to 225 days (mean 128 days) in baboons.
• Porcine cytomegalovirus (PCMV) presence did not impact xenograft survival in this cohort.
• Histological findings included adipose deposition, chronic vasculopathy, thrombosis, and acute cellular rejection in some xenografts.

Conclusions:

• 10-GE cardiac xenografts demonstrate variable survival in non-human primates, potentially due to unaddressed antigens.
• Despite variability, 10-GE pig hearts show suitability for clinical cardiac xenotransplantation.
• These organs have already been used in two human compassionate use cases.