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‘First big step’ for xenotransplantation inches forward elusive future of heart transplantation
The historic series of successful animal-to-human cardiac transplants by American surgeons starting last year indicated a breakthrough in the field of xenotransplantation, experts said, inching forward a potential solution to the shortage of human hearts for transplants
As previously reported by SummitMD, the cross-species heart transplant performed in January by the surgical team at the University of Maryland Medical Center (Baltimore, USA) made international headlines after the 57-year-old male patient survived and fared well immediately post-operation.
The patient’s extensive medical history – including chronic mild thrombocytopenia, hypertension, nonischemic cardiomyopathy and a prior mitral valve repair – excluded him from benefitting from all other standard treatment, including human heart-to-heart transplants.
We’ve taken the first big step for xenotransplants, and we’re going further than ever before, as we have with human-to-human heart transplants.
Sang-un Lee, MD, PhD
Although the medical team reported incredible improvements – including the patient “sitting alone in a chair and waving to caregivers, free from bed for the first time in 109 days” on day 49 – his death, attributed to xenograft failure of unknown cause, was announced on day 60, marking a two-month survival record.
“As with any first-in-the-world transplant surgery,” lead surgeon Bartley P. Griffith, MD (University of Maryland Medical Center, Baltimore, USA) said, “this one led to valuable insights that will hopefully inform transplant surgeons to improve outcomes and potentially provide life-saving benefits to future patients.”
Shortly after, surgical teams at NYU Langone Health, led by Nader Moazami, MD (New York, USA), reported the completion of two pig-to-human cardiac transplants for two brain-dead patients last June and July, respectively, finding no evidence of rejection days after the operation.
In all three cases, the porcine hearts were genetically modified by United Therapeutics’ owned Revivicor (Blacksburg, Virginia, USA) through a complex process known as somatic cell nuclear transfer.
Somatic cell nuclear transfer involves inactivating (“knock out”) animal genes that are incompatible with human ones and injecting (“knock in”) beneficial human genes into animals to regulate processes like coagulation and inflammation.
On the recent xenotransplants, experts noted that the innovative gene engineering methods would serve as a major stepping stone for future developments, despite the dismal length of extended survival of the actual transplant and prevailing concerns of zoonosis and immune rejection.
“Considering the first human-to-human heart transplant in 1967 lasted 18 days, we cannot call this first attempt at genetically modified porcine-to-human cardiac xenotransplantation a failure or a disappointment,” Sang-un Lee, MD, PhD (Asan Medical Center, Seoul, South Korea) told SummitMD.
Just because it took a long time to reach the starting point doesn't mean it will be a long race.
Sang-un Lee, MD, PhD
“The human heart is a biochemical organ with various functions, but it also acts as a pump,” Lee said. “Currently, the three human-to-human heart transplant strategies that could potentially replace or support failing hearts are mechanical heart pumps, autologous hearts or xenotransplants.”
Although progress has been made for the three strategies, each method carries significant drawbacks and limitations that bar use in standard medical practice, Lee said.
Mechanical heart transplants – known as left ventricular assist devices (LVADs) – are battery-powered artificial heart pumps that serve as a bridging therapy for heart failure patients who are waitlisted for an actual heart transplant.
Autologous heart valves involve securing and engineering healthy stem cells of the recipient’s heart to transplant back into the patient.
“Each strategy carries significant limitations,” he said. “Although mechanical heart pumps are used in practice, it cannot fully replace human hearts because it only functions as a pump. Autologous hearts, which covers the biochemical function of a heart, also cannot function alone because it lacks the heart’s pumping ability. Xenotransplantations carry the risk of immune rejection and zoonosis.”
“This indicates that autologous hearts should be used with mechanical heart pumps or animals engineered to support the development of the human heart structure,” he said. “It’s difficult to speculate which experimental heart transplant options will reach success first, but we can say we’ve taken the first big step for xenotransplants, allowing us to go further than we’ve gone before.
“We experienced the same trial and error with human-to-human heart transplants,” he added. “Just because it took a long time to reach the starting point doesn't mean it will be a long race.”
Elizabeth G. Phimister, PhD, the deputy editor of the New England Journal of Medicine (NEJM) also wrote: “The normal function of a pig heart in a human and the avoidance of graft rejection for more than a month is an achievement supported by decades of research in immunity, embryology, genetics, and animal husbandry.”
“The basis of genetically modifying an entire animal was established 26 years ago with the ‘cloning’ of a sheep from the nucleus of a mammary cell of a white-faced Finn Dorset sheep.
The recent xenotransplant is based on research that has unfolded over decades but it’s only recently that major challenges have been addressed, suggesting future improvements are likely.
Elizabeth G. Phimister, PhD
“It was by this means that the first pig devoid of alpha-gal was engineered, and this mutant pig has now been bred for more than 11 generations, gaining the Food and Drug Administration (FDA) approval as a New Animal Drug Application just 2 years ago.
“Although the recent xenotransplantation is based on research that has unfolded over decades, it is only recently that major challenges, such as maintaining the functionality of the donor’s heart between harvesting and transplantation, have been addressed, suggesting future improvements are likely,” she said.
Down to brass tacks: rise and fall of 1st cardiac xenotransplant
In a NEJM report published on July 7, Griffith and investigators reported that the transplant recipient had fared well post-surgery, rehabilitating without any cardiovascular support, including venoarterial extracorporeal membrane oxygenation (ECMO).
Tests showed that the xenograft functioned normally, with no evidence of immune rejection or porcine endogenous retroviruses (PERV) infection, which raised hopes of extended survival.
But vital signs dropped on the evening of day 49: venous oxygen saturation was mixed (33%); left ventricular ejection fraction (LVEF) increased to 70%; both right and left LV walls thickened dramatically; and global longitudinal strain values became increasingly abnormal, leading to recannulation for ECMO.
Suspected as an “atypical manifestation of antibody-mediated rejection,” the patient’s deterioration spurred the use of therapeutic plasma-exchange, intravenous immune globulin, complement inhibition with C1 esterase inhibitor and eculizumab, and B-cell depletion with rituximab that “appeared to prevent obvious rejection of the genetically modified xenograft.”
Although medical examinations on day 60 showed no infection with PERV or porcine circovirus 3 (PCV3), histological exams revealed scattered myocyte necrosis, interstitial edema and red-cell extravasation without evidence of microvascular thrombosis – findings “not consistent with typical rejection.”
The case provides a glimpse of how quickly and profoundly genetic and biologic engineering, along with cell and developmental biology, can be marshalled to attack problems in medicine.
Jeffrey L. Platt, MD & Marilia Cascalho, MD, PhD
“The pronounced sudden diastolic failure and global pathologic myocardial thickening without systolic dysfunction remain unexplained,” Griffith wrote. “These findings, in combination with focal capillary injury in the virtual absence of complement deposition, are not normally seen in human allotransplantation.”
“Endomyocardial biopsies of the xenograft did not show acute cellular or antibody-mediated rejection, and no complement staining was identified until a week after the late dysfunction that led to ECMO support.”
Pursuing autopsy revealed the xenograft had swelled nearly double in weight. Investigators also noted that the patient showed low levels of infection with porcine cytomegalovirus (pCMV) – known as suid herpesvirus 2 (SHV-2) – starting on day 20 that increased over time.
“Detection of pCMV was unexpected given the husbandry practices, negative surveillance PCR testing of nasal swab specimens from the donor animal before organ transplantation, and the use of antiviral prophylaxis,” they said. “Presence of pCMV in explanted xenografts from nonhuman primate recipients has been correlated with worse outcomes than an absence of pCMV, for unclear reasons.”
“Further viral testing is warranted because human herpesvirus 6 (HHV-6), which has been shown to cross-react with pCMV and to be associated with allograft rejection, was also detected in a lung-lavage specimen from this patient,” investigators wrote.
Extracting and applying lessons learned
In an accompanying editorial, Jeffrey L. Platt, MD and Marilia Cascalho, MD, PhD (University of Michigan Ann Arbor, USA) wrote: “Given past failures, one might justifiably ask whether this recent xenotransplantation provides a glimpse at the future treatment of organ failure, or merely fulfills the longstanding quip that xenotransplantation is and always will be the future of transplantation.”
“Regardless, it provides a glimpse of how quickly and profoundly genetic and biologic engineering along with cell and developmental biology can be marshaled to attack problems in medicine,” they said.
“A more important question may be whether techniques used to engineer pigs could be applied to generating human tissues and organs for implantation into patients with organ failure,” they asked. “Pluripotent stem cells and other cell types are increasingly explored for the generation of autologous organs through organogenesis or three-dimensional tissue engineering.”
A more important question may be whether techniques used to engineer pigs could be applied to generating human tissues and organs for implantation.
Platt & Cascalho
“Use of autologous organs modified to resist underlying disease would presumably avert the need for — and toxic effects of — lifelong immunosuppression. The advent of such autologous implants would be likely to decrease the demand for allotransplantation.”
Autologous organs could also “ironically” increase the demand for reverse xenografts (animals engineered to support the development of human tissues) and xenografts by acting as temporary, bridging therapies for patients waiting on autologous transplants, they said.
Going forward, research on methods to apply the utilized genetic modification techniques to humans and reducing the extent of genetic modification in pig genes could help improve long term outcomes, they said:
“Several steps could advance clinical application of xenotransplantation for whatever purposes xenografts might fulfill. Reduction in the number and extent of genetic modifications of pigs could benefit the long-term function of xenotransplants, since the untoward insertion of genetic sequences has been associated with myocardial aging.
“Still more important will be efforts to decrease the intensity and toxicity of immunosuppression. Since immunity to xenografts may engage narrower pathways of T-cell activation than allografts, perhaps immunosuppression can be focused to reduce longer-term toxic effects for recipients and grafts and possibly autografts.”
August 31, 2022 6331
