Xenografts: Discussing life-saving potential of cross-species transplants amid safety concerns

Key Takeaways

  • The global shortage of transplantable organs has reached alarming levels, leaving thousands of individuals languishing on transplant waiting lists.

  • Amidst these concerns, on September 20, 2023, surgeons successfully implanted a genetically modified pig's heart into a human patient for the second time ever.

  • The xenotransplant was done under the FDA’s “compassionate use” regulation and offers a glimmer of hope for terminal patients, but ethical and safety concerns remain.

In September 2023, for the second time in history, surgeons successfully transplanted a genetically altered pig's heart into a human recipient.[] The success of this xenotransplant, or cross-species transplant, offers a glimpse of hope for patients facing a dire shortage of available organ donors. 

However, safety concerns remain, primarily due to the risk of organ rejection by the recipient's immune system.

Sensitivity tests, new technologies in genetic engineering, and updated screening guidelines show promise in reducing these risks. 

Xenografts' life-saving potential

The patient, Lawrence Faucette, was a 58-year-old man suffering from end-stage heart disease who was ineligible for a human heart transplant due to pre-existing vascular issues and internal bleeding complications. Following his transplant, however, he was able to breathe unassisted, and his newly transplanted heart operates without mechanical aid. 

This success story follows on the heels of the first pig-to-human heart transplant, which took place in January 2022.[] The recipient, however, passed away 2 months after his surgery, possibly due to a pig virus known as porcine cytomegalovirus (PCMV). As a result, researchers have implemented more sensitive tests to screen donor organs for the virus. 

In better news, the success of Faucette’s transplant represents a potential answer to the ongoing organ shortage.

The organ shortage crisis

Solid organ transplantation has been a reliable solution for end-stage organ failure for over half a century. Despite a 134% increase in organ donations in the US since 1995, the number of people awaiting transplants still surpasses available organs.[]

According to the US Health Resources & Services Administration, 17 people die each day while waiting for an organ transplant. Every 10 minutes, someone new joins the transplant queue.[]

The latest data indicates that 113,922 individuals are on the US organ transplant waiting list.[] Most of them require kidney transplants (96,147), followed by liver (10,251) and heart transplants (3,384).

High demand, low supply

The conventional reliance on human donor organs is insufficient to meet the ever-increasing demand. Xenografts present a potential solution to this crisis.

Experts writing in the journal of the Institute for Laboratory Animal Research (ILAR) present a thorough discussion of this topic.[]

Xenografts are a type of graft or transplant in which living tissue or organs are transferred from one species to another. The most commonly explored xenografts include pig hearts, kidneys, islets, livers, and lungs to address the shortage of human organ donors. 

To make xenotransplants feasible, genetic modification of pigs' genes is crucial. CRISPR-Cas9 and somatic cell nuclear transfer (SCNT) technologies are being utilized to streamline pig genome editing, making them more human-compatible and helping to overcome antigen incompatibility.

Reverse xenotransplantation involves transplanting human cells into animals like pigs, which is another unique method to create organs for transplantation.

Barriers to xenotransplantation

One of the primary concerns in xenotransplantation is the risk of organ rejection by the recipient's immune system, ultimately leading to organ failure. The recipient's natural killer cells and T cells, as well as ischemia-reperfusion injury occurring during transplantation, trigger the host's innate immune response, which potentially recognizes the graft as foreign. 

Human natural antibodies, specifically those targeting Galα1-3Gal, can lead to immediate rejection, especially when complement regulation fails. Genetic engineering of pigs lacking Galα1-3Gal shows promise in reducing this rejection.

In addition to immune-related challenges, infectious agents, particularly viruses, can transfer from the graft to the recipient. The porcine endogenous retrovirus (PERV) and PCMV can transmit from pig graft to human cells.

As xenotransplantation approaches clinical use, the focus shifts from preventing acute rejection to ensuring long-term graft functioning while avoiding chronic diseases. This involves finding effective immunosuppressive methods and ways of inducing immune tolerance, but long-term survival remains challenging.

The heart transplanted into Faucette was prepared with 10 genetic modifications to reduce the chances of rejection.

The patient’s medical team also used a novel experimental antibody, tegoprubart, that inhibits a specific protein involved in triggering immune responses.

Ethical ramifications

Both heart xenotransplants were performed under the FDA's “compassionate use” regulation, offering a glimmer of hope to terminal patients.[]

"Compassionate use," sometimes called “expanded access,” is a possible avenue for patients grappling with a severe, potentially life-threatening ailment to acquire experimental medical treatments, be they drugs, biologics, or medical devices. This option becomes viable when no comparable or satisfactory therapies are at their disposal outside of clinical trials, and the potential benefits for the patient outweigh the possible treatment risks.

According to a group of clinicians publishing in The Hastings Center Report, patients' understanding and consent are crucial; they must be fully aware of the risks and benefits, and their participation should be voluntary.[]

Fair access to these experimental therapies is vital, and it's important to avoid discrimination, as physicians. Monitoring for infectious diseases and allowing patients to withdraw from clinical trials at any time is essential to protecting their rights. 

Several factors are vital to meeting the ethical standards surrounding xenotransplantation. These include transparent decision-making, oversight by regulatory authorities and ethics committees, and accountability for ethical choices throughout the process. 

What this means for you

With advances in medicine accompanying an increase in aging populations, the demand for organs, particularly for the heart and kidneys, continues to rise. Xenotransplantation could be a solution, and may be especially valuable in regions where organ donation is limited. As physicians' experience with xenotransplantation evolves, the expected cost-effectiveness might further drive demand.

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