By Heather S. Loring, PhD, Xinyu Huang, Balazs Felcsuti, and Sheela Hegde
- As the waitlist for transplantable organs continues to grow, with only half on the waitlist receiving transplant within 5 years, there remains significant unmet need to increase the quantity of viable organs and extend patients’ lives.
- After years of technological advancements facilitated by genome editing, xenotransplantation holds the promise to be part of the solution to alleviate the severe organ shortage.
- Xenotransplantation is especially promising in End Stage Kidney Disease, which accounts for over 85% of the organ waitlist.
- Xenotransplantation could supplement allotransplantation by expanding the number of viable organs for transplantation and providing an option for patients who cannot currently receive a human organ.
- As xenotransplantation could cannibalize hemodialysis but expand the market for therapeutics that support graft survival, such as immunosuppressive drugs, the technology has the potential to serve as both a market disrupter and expander.
Diseases, such as polycystic kidney disease, cystic fibrosis, and heart defects, or injury can disrupt normal organ function. Prior to the advent of organ transplantation, treatment for organ dysfunction was limited. As an example, the duration of dialysis for kidney disease was restricted by the destruction of the patient’s vasculature.1 It was not until 1954 that the first kidney allotransplantation was successfully performed between identical twins, improving long-term glomerular filtration.2 Liver, heart, and pancreas transplants followed in the 1960s and lung and intestinal organs in the 1980s. However, utilization was limited by the lack of a viable system for organ matching, the risk of organ rejection, and infection. The launch of United Network for Organ Sharing (UNOS) and improvements in prevention and treatment of rejection drastically improved the outlook for organ transplantation and life expectancy for diseases associated with organ failure.2 However, there remains significant unmet need as demand far outstrips the supply of donor organs, resulting in long patient waitlists. Xenotransplantation has been in development for decades, and recent progress suggests that it could eventually be a major part of the solution to alleviate the global organ shortage and improve patient outcomes.
High Unmet Need for Transplantable Organs
Today, transplantable organs typically come from deceased or living human donors. Given the scarcity of such organs, the list of patients waiting for organ transplants has been growing steadily at 2% a year for the past decade (Figure 1).3
Transplants have increased ~4% annually over the same ten-year period; however, this has not been sufficient to keep pace with the growing flow of additions each year (Figure 1).3 Transplant growth exceeds waitlist expansion across the board for the four most commonly transplanted organ types. However, sufficient unmet need remains as the total number of patients eligible for transplantation is somewhere between 2-3x the number of actual organ recipients depending on the organ (Figure 2). The need is greatest for kidneys as the waitlist is the largest relative to transplants (1.7x) despite representing ~60% of the overall transplant market and transplants growing 4% annually over the last decade. Comparatively, the liver waitlist was 1.5x the number of transplants last year, followed by heart (1.3x) and lung (1.2x).3 As a result of the current waitlist size and continued growth, the backlog of patients waiting for transplant is growing steadily.
Patients are typically added to the national waitlist after a physician has ruled out other treatment options. For example, patients with end stage renal disease (ESRD) are typically eligible when they have a glomerular filtration rate (GFR) of <20%.4 With cardiovascular diseases, patients are listed if intravenous (IV) medications or a ventricular assist device (VAD) is needed to support ventricular contraction. Upon addition to the waitlist, 67% of patients will wait longer than a year for an organ transplant, with 13% of patients waiting more than 5 years (Figure 3).3
As waitlist duration increases, patients’ health deteriorates, comorbidities emerge, and the incidence of negative disease outcomes increase (Figure 4).3 By year 5, only 48% of patients will have received a transplant and the remaining 52% of patients will have died, been removed, or remained on the waitlist. In addition, transplanted patients whose graft has failed can be added back to the waitlist, increasing the overall backlog.
Given the significant need to improve patient outcomes, xenotransplantation offers an attractive solution as it could drastically increase the number of viable organs for transplantation and reduce time spent on the waitlist.
History of Xenotransplantation
Xenotransplantation has undergone significant development since the first animal-to-human blood transfusion in 1667, skin grafts in the 1880s, and kidney transplants in the 1960s (Figure 5).5-6 However, despite extensive research and development efforts, the practical utility of xenotransplantation has long been hampered by issues with host rejection and mortality.
After the failed baboon heart transplant in 1983, the field transitioned from primate hosts to porcine due to differences in organ size and concern of infectious disease transmission.5 However, in the 1990s the field discovered that, contrary to humans, non-primate mammals express an oligosaccharide, α-1,3-galactose (α-Gal), on cells and tissues, which stimulates an immune response and ultimate destruction of the xenograft.6 Additionally, the discovery of pig endogenous retroviruses (PERV) in the late 1990s led to concerns for cross-species transmission of porcine viruses and resulted in a large-scale shift away from research and development efforts in xenotransplantation.7 Progress stagnated until the discovery of genome editing tools (e.g., ZFNs, TALENs, CRISPR-Cas9) that could edit PERV sequences to prevent viral transmission and mutate common xenoantigens that initiate human immune responses, such as α-Gal, cytidine monophospho-N-acetylneuraminic acid hydrolase (CMAH), beta-1,4-N-acetylgalactosaminyltransferase 2 (β4GalNT2), and beta-2-microglobulin (β2M).8-15 Additionally, introduction of human transgenes into the pig genome to reduce blood clotting (e.g., TBM, EPCR) and inflammation (e.g., DAF, CD46, HO1, CD47) in the transplanted organ were performed to increase odds of success.
Current Xenotransplantation Landscape
With these technological advances came the first xenotransplant of a kidney to a brain-dead host and a xeno heart to a living recipient, in late 2021 and early 2022, respectively.16-18 There were no signs of rejection or viral transmission with the kidney xenotransplant, and normal function was evident with increases in GFR and creatine clearance. These findings suggest that the main barriers impeding xenotransplantation had been surmounted with the advent of genome editing technologies. A few months later, news broke that the first xeno heart transplant was performed under FDA authorization of compassionate use; however, this transplant did not prove to be successful long-term.18 The patient survived for two months post-transplant and ultimately was found to have signs of porcine cytomegalovirus, which could have contributed to his demise.19 Future efforts will focus on more comprehensive viral evaluation of the donor prior to transplant.
The xeno heart, provided by Revivicor, was genetically modified to remove three genes involved in the production of oligosaccharide xenoantigens, remove a porcine growth hormone receptor to reduce the chance of the organ outgrowing the chest cavity, and include six human genes involved in blood coagulation and inflammatory response (Table 1).20 However, Revivicor did not modify the 62 PERV sequences as the risk was deemed insubstantial. In addition to Revivicor, several other companies operate in the xenotransplantation space, approaching development of porcine donor organs from different angles. eGenesis’ approach involves genetic modifications to knock out the carbohydrate xenoantigens and reduce coagulation and immune response, in addition to inactivating all PERV sequences to eliminate risk of retroviral transmission.21 Recombinetics/Makana are also developing xenokidneys but focus on only eliminating the three carbohydrate xenoantigens.22 Interestingly, Xenotherapeutics has concentrated on only knocking out α-Gal in their xeno skin and xeno nerve products, while Qihan Biotech focuses only on the elimination of PERV sequences.23-24 Finally, Miromatrix has documented no effort toward genetic modifications in their porcine scaffolds, potentially due to the fact that these are recellularized with human cells.25 Despite the range of approaches, it remains unclear which modifications or lack thereof will be the most successful in the clinic.
In addition to these companies making strides via preclinical trials in animals, the past decade has been marked by numerous xenotransplant clinical trials for skin, kidney, islet cells, and beyond, with porcine organs the primary donor of interest (Figure 6).26 Further trials are bound to come with the recent progress and headlines. Of note, Revivicor anticipates launching a multicenter clinical trial for xeno heart transplants by the end of 2023.27 In the meantime, if another patient qualifies for a xenotransplant based on severity of disease and exclusion from the transplant registry, the physician involved in the initial xeno heart transplant plans to apply to the FDA for another one-time authorization of compassionate use for the procedure.
Impact of Xenotransplantation on ESRD Treatment Paradigm
Given that kidney programs are the most common focus across players in the xenotransplantation space, xeno kidneys will likely be the first to be broadly commercialized. This focus is not surprising given the significant unmet need in ESRD, with patients waiting for kidneys accounting for approximately 85% of today’s waitlist and only about 60% of transplants as of June 2022 (Figure 7).3
This problem is only expected to worsen as ESRD is projected to increase ~2% annually due to increasing incidence of correlated diseases (e.g., diabetes, heart disease, high blood pressure) and stagnant supply of deceased and living donor kidneys.28 ESRD patients typically endure dialysis for 3-7 years while awaiting a human organ transplant. Xenotransplantation particularly has the potential to reduce waitlist duration and improve outcomes for patients that begin dialysis later in their treatment journey. Additionally, xenografts could cater to patients that are difficult to match, such as human leukocyte antigen (HLA) positive patients. Assuming an average of 5-year graft survival, an arguably ambitious goal, xenotransplantation could address 30-50% of patients currently on the waitlist. This would improve clinical outcomes overall by reducing waitlist time and comorbidities, like heart disease and nerve damage that can interfere with transplant eligibility (Figure 4). Reducing waitlist time would also decrease mortality as the five-year survival rate on dialysis is less than 50%, while renal allotransplants have survival rates close to ~90% at ten years.29
In addition to improving clinical outcomes, xenotransplantation could help alleviate the ongoing financial burden of ESRD. Dialysis is an expensive ongoing treatment with costs upwards of $90,000 each year. Xenotransplantation has the potential to mitigate the health economic burden of ESRD by decreasing the number of patients on dialysis. Based on current economic studies and projected cost of xenotransplantation at ~$110,000, it would only take ~2 years of graft survival for xenotransplantation to be more cost effective than dialysis (Figure 8-9).30-32
Aside from improved clinical outcomes and reduced financial expenditures, xenotransplantation could improve overall quality of life for these patients by freeing them from frequent hemodialysis and related comorbidities. As this one-time curative procedure would replace the bane of recurrent treatment that is associated with catheter-related infections and development of comorbidities, there is a net gain in quality-adjusted life year (QALY) of 0.65 after 5 years of graft survival (Figure 10).
The advent of xenotransplantation would improve clinical outcomes, alleviate the global economic burden of ESRD, and enhance patient quality of life. The compilation of these factors results in considerable tailwinds driving a shift in the treatment paradigm. While xenotransplantation could disrupt the hemodialysis market, xeno kidneys are unlikely to replace allotransplantation within the foreseeable future due to the comparative cost advantage of allo organs and the need for xeno to generate long-term clinical and real-world data. Therefore, as a supplement to allotransplantation, xenotransplantation could expand the market for transplant-related services and therapeutics multifold, given the number of waitlist patients relative to human transplant recipients.
With the significant advancement made in the xenotransplantation space over the past decade, xenotransplantation could become reality in the near future and help address the ongoing organ shortage. Upon its approval, xenotransplantation is expected to expand the transplant market by targeting the patient backlog. In the long run, the technology may eventually serve as an alternative to allotransplantation if the risk of graft rejection or infection proves lower and graft survival longer than in allotransplantation. As this would require long-term clinical and real-world data, xenotransplantation will likely co-exist with allotransplantation for the foreseeable future. By doing so, it would significantly expand the market for transplantation-related services and therapeutics, including immunosuppressants, treatments for graft versus host disease, antibody-mediated rejection, and desensitization. Although xenotransplantation must still overcome significant developmental challenges, it promises to open a new frontier in managing organ transplantation and related conditions.
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Heather Loring, PhD, Senior Analyst in Health Advances’ Boston office.
Xinyu Huang, Senior Analyst in Health Advances’ Boston office.
Balazs Felcsuti, Partner in the Boston office and co-leads Health Advances’ Metabolic and Autoimmune Diseases Practice.
Sheela Hedge, Partner and Managing Director in the Boston office and co-leads Health Advances’ Metabolic and Autoimmune Diseases Practice.