Rethinking preclinical models for genetically engineered porcine red blood cell xenotransfusion

Area of Science:

• Biomedical Engineering
• Transfusion Medicine
• Xenotransplantation

Background:

• Genetically engineered porcine red blood cells (pRBCs) are being developed for transfusion medicine.
• Triple-knockout (TKO) pigs lacking key xenoantigens and expressing human protective molecules show reduced antibody binding.
• Current translational development is hindered by the lack of appropriate in vivo evaluation models.

Purpose of the Study:

• To discuss the limitations of current preclinical models for evaluating pRBC xenotransfusion.
• To propose a purpose-specific translational framework for advancing pRBC xenotransfusion.
• To highlight the need for integrated testing strategies.

Main Methods:

• Review of existing preclinical models for xenotransplantation, including Old World and New World nonhuman primates.
• Discussion of the immunological barriers and limitations associated with these models.
• Proposal for a multi-faceted translational framework incorporating various testing modalities.

Main Results:

• Old World nonhuman primates may not accurately represent human immune responses to pRBCs due to CMAH-positive background.
• New World nonhuman primates, brain-dead human models, and early human studies present distinct advantages and limitations.
• A single preclinical model is insufficient for robust evaluation of pRBC xenotransfusion.

Conclusions:

• A purpose-specific translational framework is essential for advancing pRBC xenotransfusion.
• This framework should integrate standardized compatibility testing, in vitro human assays, and animal-based safety stress-testing.
• Ethically and legally feasible short-term human reference models should be considered.