‘Comprehensive framework’ needed to spur more xenotransplantation research
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Researchers are calling for the creation of a comprehensive framework to address current barriers to xenotransplantation in clinical practice, including issues of rejection, infection, legal regulations, informed consent and animal rights.
In a state-of-the-art review published in JACC: Basic to Translational Science, researchers noted the heightened interest in xenotransplantation after reports of the first human to receive the heart of a genetically modified pig in January, a moment that came after decades of failure in experimental animal models.
“We believe that if the regulatory, scientific and ethical barriers can be overcome while keeping this technology cost-effective, it not only opens up a new donor organ source to service the transplant waitlist, but more importantly provides an option for those otherwise optionless at this time,” Mandeep R. Mehra, MD, MSc, The William Harvey Distinguished Chair in Advanced Cardiovascular Medicine and medical director of Brigham and Women’s Hospital Heart and Vascular Center and professor of medicine at Harvard Medical School, told Healio. “Such examples could be those with cancer with HF and no option for either human heart transplant or a left ventricular assist device due to biventricular failure, repeat transplant candidates who are older, those who are sensitized with antibodies that prevent a human transplant or those with congenital heart disease who are not immediately clear candidates for either mechanical circulatory support or transplant.”
First pig-to-human heart transplant
As Healio previously reported, a man with terminal heart disease who was deemed ineligible for a conventional heart transplant became the first in the world to receive a genetically modified pig’s heart in January, a milestone for xenotransplantation. The man, David Bennett, aged 57 years, died 2 months after the procedure.
In a statement released after the man’s death, the University of Maryland School of Medicine and the University of Maryland Medical Center said the transplanted heart performed very well for several weeks without any signs of rejection. Bennett reportedly spent time with family and participated in physical therapy.
The researchers noted that overcoming hyperacute, acute humoral and acute cellular xenograft rejection is central to the success of cardiac xenotransplantation, as well as overcoming the problems of complement-mediated toxicity, dysregulated coagulation, perioperative cardiac xenograft dysfunction and the need for novel immunosuppressive medication.
“As the research in xenotransplantation progresses and porcine xenograft survival in nonhuman primates and humans is extended, there are hemodynamic and physiological dissimilarities that will likely be uncovered,” the researchers wrote. “As an example, which complicates thoracic xenografts, the blood pressure difference between pigs and primates leads to detrimental xenograft overgrowth. Not only blood pressure but also body temperature differs between pigs and humans, and a decrease of 2°C could potentially induce metabolic derangements in porcine xenografts once transplanted into humans.”
Ethical, financial challenges
The researchers noted that a “comprehensive framework” for future clinical trials is needed, given the complexity of between-species transplantation and recent advances in xenotransplantation. Although risk for disease transmission from animals to humans is considered minimal, other questions remain, including whether to move forward with xenotransplantation in another human recipient and how to select appropriate patients.
“The first issue we must contend with is whether we are ready to move to the next xenotransplantation in a human,” the researchers wrote. “We strongly believe this to be the case. As the history of evolution of cardiac allotransplantation or mechanical circulatory support attests, advances occur incrementally rather than in a transformative manner. It is critical that the most appropriate patient be matched to the technology while exercising vigilance for novel challenges that will nevertheless surface.”
The authors wrote that ideal cases will be patients with advanced HF who are ineligible for cardiac allotransplantation or destination-therapy durable left ventricular assist devices.
Development of sensitive and specific laboratory testing will also be critical to monitor xenograft function, as any immunotherapy required will be distinct from that used in allotransplantation.
Ethical questions also remain; there is currently no guideline in place to dictate legal regulations of pig-to-human heart xenotransplantation, and uniform social acceptance of the practice is unlikely. Differences in cultural and religious beliefs will make it particularly challenging to build consensus guidelines on xenotransplantation, the researchers wrote.
“The current barriers are in understanding the science of immunosuppression with such transplants, detecting and monitoring for porcine infections that can be transmitted to the human pool, costs associated with acquiring the organs, regulations surrounding quality control and ethical considerations as well as physiological challenges of adaptation to human stress with exercise and BP regulation,” Mehra told Healio.
The researchers wrote that xenotransplantation offers great potential; however, careful clinical studies will be needed to assess whether long-term outcomes rival currently available alternatives, including mechanical circulatory support devices and marginal or currently discarded human donor hearts.
For more information:
Mandeep R. Mehra, MD, MSc, can be reached at mmehra@bwh.harvard.edu.
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