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Xenotransplantation

Numerous strategies to increase human donor organ supply have not closed the staggering supply-demand gap that only continues to increase. Human donor organs may never fully meet demand. Xenotransplantation is one approach that has the potential to sufficiently address the organ shortage crisis.

Xenotransplantation is the transplantation of living organs, tissues, or cells from one species to another. Pigs have been identified as a good species for xenotransplantation due to their similarity to humans in terms of organ structure and physiology, in addition to the abundance of the species.

In the past, two key hurdles have prevented successful xenotransplantation:

  • The potential risk of the transmission of viruses between species
  • Immune-mediated incompatibilities between species leading to organ rejection

Recent innovations in gene-editing technology enable more precise yet more feasible editing of the genome than was ever before possible.1 At eGenesis, we are harnessing this innovation to tackle both of the hurdles that have prevented the advancement of xenotransplantation to date and to create Human Compatible (HuCo™) organs and cells to address the transplant shortage crisis.

The history of xenotransplantation

Successful xenotransplantation has been a goal for centuries.

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Obstacles to successful xenotransplantation

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Each cell in a transplanted porcine organ carries the possibility of endogenous retroviral transmission to normal healthy cells in the human recipient.

Virus transmission

A pig’s genome includes an endogenous retrovirus that is harmless to the pig but could pose a risk to humans.4 The transmission of other viruses is also a risk, but it can be managed by using a regulatory-compliant, biosecure supply chain.

Immune-mediated organ rejection

Rejection occurs due to a mismatch between the host immune system and the donor organ or cells. Patients receiving a porcine organ or cells without genetic modifications would die within minutes to hours after the transplant.5,6 The human body’s immune-mediated rejection of a xenograft can occur across a few key mechanisms.5,6

Hyper Acute Rejection

Hyper-acute rejection

Within hours of a transplant, hyper-acute rejection can occur through the activation of the innate and adaptive immune systems, including preformed antibodies.5,6 The innate and adaptive immune systems are the human body’s natural defense mechanisms against invading organisms.

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Vascular injury

The activation of the complement system, which is another component of the immune system, and a mismatch between the donor and host immune systems can lead to coagulation dysfunction.5,6 When blood coagulates improperly, it can block proper blood flow and circulation, which can cause injury to blood vessels.

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Cell-mediated chronic rejection

Cells of the innate and adaptive immune systems can attack and reject an organ over a longer period. While it is a similar process to hyper-acute rejection, it is a slower process that can degrade the quality and functionality of the transplanted organ. Over time, increased systemic inflammation can cause chronic rejection.5,6

Expert voices

For many years, the scientific and medical communities have supported the advancement of safe and effective xenotransplantation procedures. The leading experts, George Church, Ph.D. and Jim Markmann, M.D., Ph.D., share their perspectives on the challenges and opportunities of xenotransplantation and the technologies that are driving innovation in this area.

George Church

Jim Markmann

References

  1. Meier RPH, Muller YD, Balaphas A, et al. Xenotransplantation: back to the future? Transpl Int. 2018;31(5):465-477. doi:10.1111/tri.13104
  2. Cooper DKC, Ekser B, Tector AJ. A brief history of clinical xenotransplantation. Int J Surg. 2015;23(Pt B):205-210. doi:10.1016/j.ijsu.2015.06.060
  3. Schuurman H-J. Regulatory aspects of clinical xenotransplantation. Int J Surg. 2015;23:312-321. doi:10.1016/j.ijsu.2015.09.051
  4. Denner J, Tönjes RR. Infection Barriers to Successful Xenotransplantation Focusing on Porcine Endogenous Retroviruses. Clin Microbiol Rev. 2012;25(2):318-343. doi:10.1128/CMR.05011-11
  5. Griesemer A, Yamada K, Sykes M. Xenotransplantation: Immunological hurdles and progress toward tolerance. Immunol Rev. 2014;258(1):241-258. doi:10.1111/imr.12152
  6. Lu T, Yang B, Wang R, Qin C. Xenotransplantation: Current Status in Preclinical Research. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.03060