International Human Xenotransplantation Inventory: A 10-year Follow-up

Abstract

Background. 

Following the recommendations by a panel of experts gathered by the World Health Organization in 2005, an inventory was established to collect practices of human xenotransplantation worldwide (www.humanxenotransplant.org). The website was activated in October 2006, in collaboration with the International Xenotransplantation Association, the University Hospital Geneva, and the World Health Organization. A first report on the collected xenotransplantation activities was published in 2010 in the journal Transplantation. In 2020, the website was redesigned, and its hosting and management were transferred to the Sichuan Provincial People’s Hospital.

Methods. 

We collected information from publications in scientific journals, presentations at international congresses, the internet, and declarations of International Xenotransplantation Association members on xenotransplantation procedures in humans performed over the past 10 y.

Results. 

A total of 5 new applications of human xenotransplantation were identified, with pig as source animal in all applications. The procedures involved transplantation of islets of Langerhans, skin, cornea, and choroid plexus cells. The treatments were performed in China, United States, New Zealand, and Argentina. No major complications or deaths were reported.

Conclusions. 

Several clinical applications of cell or tissue xenotransplantation are ongoing around the world. Compared with the previous reported period (1995–2010, with 29 activities, mostly without governmental regulation), the recent number of clinical activities was reduced, and all were officially approved. This information should be used to inform healthcare officials, staff, and the public with the objective of encouraging good practices based on internationally harmonized guidelines driven by initiatives such as the Changsha Communiqué.

INTRODUCTION

Organ transplantation remains the gold standard treatment for end stage organ failure, such as heart, lung, liver, or kidney failure. With an ever-increasing number of patients waiting for various organs, there is a significant imbalance between the number of patients on the waiting list and the number of available donated transplantable organs, which results in longer waiting times and higher death rates while on the waiting lists.

One potential solution to resolve this issue could be xenotransplantation, which provides sufficient organ availability and also eliminates the associated issues such as organ trafficking. However, it also carries the possible risk of zoonosis.

Following the recommendations by a panel of experts gathered by the World Health Organization (WHO) in 2005,¹ an inventory was established with the aim to collect practices of human xenotransplantation worldwide (www.humanxenotransplant.org).²

This inventory has collected information from various sources including publications in scientific journals, presentations at international congresses, the internet, and declarations of International Xenotransplantation Association (IXA) members on xenotransplantation procedures in humans performed from the year 1995. A total of 29 applications for undertaking clinical xenotransplantation were identified between 1995 and 2010. These procedures involved transplantation of xenogeneic products, that is, islets of Langerhans, kidney cells, chromaffin cells, embryonic stem cells, fetal, and adult cells from various organs or extracorporeal perfusion using hepatocytes, liver, spleen, or kidney. The treatments were performed in 12 different countries, 9 of them having no national regulations for xenotransplantation.

The inventory highlighted the fact that several clinical applications of cell xenotransplantation were ongoing around the world, often without any clear governmental regulation nor oversight from any regulatory body. This information was used to inform national health authorities, healthcare staff, and the public, with the objective of encouraging best practice, with internationally harmonized guidelines and regulation of xenotransplantation practices.

This present article aims to present a 10-y follow-up of the inventory and present the recent applications of human xenotransplantation between 2010 and 2020.

MATERIALS AND METHODS

The website (www.humanxenotransplant.org) was initially activated in October 2006, in collaboration with the IXA, the University Hospital Geneva, and the WHO. An electronic form was available on the website to submit new data. The information of a new practice was collected by both actively using online resources and passively by collecting reports about the practice. In 2020, the website was redesigned, and its hosting and management were transferred from the University Hospital Geneva to the Sichuan Provincial People’s Hospital in China. We collected information from publications in scientific journals, presentations at international congresses, the internet, and declarations from IXA members on xenotransplantation procedures undertaken on humans performed over the period from January 2010 to December 2020.

RESULTS

From January 2010 to December 2020, we identified a total of 4 applications of human xenotransplantation (Table 1). The source animal used were pigs in all applications (n = 5). The procedure types involved transplantation of islets of Langerhans (n = 2, in 54 patients), skin (n = 1, in 6 patients), cornea (n = 1, in 25 patients), and choroid plexus cells (n = 1, in 12 patients). The treatments were performed in China (n = 2), and in the United States (n = 1), in New Zealand (n = 2), and in Argentina (n = 1).

TABLE 1. - List of human xenotransplantation worldwide from September 2009 to June 2020

Type of cells, tissue, or organ	Animal source	Primary author	Country and time of report	Source of information	Therapeutic purpose	Number of patients	Exposure to xenogeneic cells	National regulation
Choroid plexus cells	Pig	R. Elliott, B. Snow	New Zealand, 2013	Congress, publications3,4	Parkinson’s disease	12	Cell transplantation, encapsulation	Yes
Islets of Langerhans	Pig	S. Matsumoto	New Zealand, 2009 Argentina, 2011	Publications	Diabetes	14 8	Cell transplantation, encapsulation	Yes Yes
Islets of Langerhans	Pig	W. Wang	China, 2013–2017	Press conference5	Diabetes	22+10	Cell transplantation	Yes
Cornea	Pig	Q. Zheng	China, 2013–2014	Publication6	Fungal keratitis	25	Tissue transplantation	Yes
Skin	Pig	J. Goverman	United States, in progress	Internet7,8	Burn	6	Tissue transplantation	Yes

Islets of Langerhans

Wang et al⁹ reported in 2011 the transplantation of neonatal porcine islets of Langerhans into 22 patients with type 1 diabetes. The study was carried out between 1999 and 2005, and the article was published after having brought back 6 patients for follow-up studies after 4–6 y. The authors reported reduction of exogenous insulin need and HbA1c levels for all 14 patients treated with cyclosporine, mycophenolate mofetil, and prednisolone. They also observed no serious adverse events nor evidence of porcine endogenous retroviruses (PERVs) transmission.

Wang et al also reported in a press conference in 2017 on a second study of transplantation of neonatal porcine islets of Langerhans into another 10 patients with type 1 diabetes from 2013 to 2017. The authors described a decrease of exogenous insulin requirements of >60% and significant improvement of these patients’ condition.

Matsumoto et al¹⁰ reported in 2014, the transplantation of encapsulated porcine islets of Langerhans into 14 patients with type 1 diabetes, without the use of immunosuppressive therapy. The study was conducted between 2009 and 2011 in New Zealand, and the authors reported a decrease in unaware hypoglycemia events and no signs of PERV transmission but no apparent effect on HbA1c levels.¹¹

Matsumoto et al subsequently reported in 2016 a study performed in Argentina, with 8 type 1 diabetes patients who received different doses of encapsulated porcine islets of Langerhans, again without immunosuppressive drugs.¹² The authors observed improved HbA1c levels in some patients with a follow-up up to 600 d and no evidence of PERV infection.¹³

Skin

In 2019, the Massachusetts General Hospital reported the transplantation of genetically engineered porcine skin directly onto a human wound, in a procedure led by J. Goverman in collaboration with the company XenoTherapeutics.⁷ The website for this phase 1 clinical trial reports an estimated enrollment of 6 patients.⁸ The xenograft was compared with skin from a deceased donor in its ability to stabilize a wound while waiting for permanent closure with the patient’s own skin. Both skin grafts were indistinguishable from each other, and no adverse events were reported.

Cornea

Zheng et al recently evaluated the effects of keratoplasty with porcine corneal tissue for the treatment of fungal keratitis combined with the use of tacrolimus. Between 2013 and 2014, the authors transplanted acellular porcine corneal stroma into 25 patients and observed transparent grafts in 20 patients at 1-y follow-up.⁶

Choroid Plexus

In 2013, the company Living Cell Technologies, led by R. Elliott, began to work on transplantation of encapsulated neonatal porcine choroid plexus cells for the treatment of Parkinson’s disease. Their work was first presented in 2013, during a congress of IXA in Osaka, Japan,¹⁴ and led in 2019 to a publication during the phase IIb of their work on these cells and short communication on its long-term follow-up in 2021.^3,4 In this last study, 12 patients received different doses of microcapsules containing neonatal porcine choroid plexus cells, implanted bilaterally in the putamen using a catheter system inserted via a cranial burr hole. The clinical trial was registered with clinicaltrials.gov and approved by a New Zealand ethics committee. The study failed to demonstrate clinical efficacy at its initial 26-wk follow-up and at 104 wk postimplant. In the follow-up, no evidence of xenozoonosis transmission was detected.

DISCUSSION

In the late 1990s, the WHO focus was drawn to the field of xenotransplantation by the international transplant community, mediated through the efforts of The Transplantation Society (TTS). In parallel, leaders in the newly emerging xenotransplantation field formed the IXA whose first meeting coincided with the XVII International Congress of TTS in Montreal in 1998, where IXA was formally incorporated as the first official “section” within TTS.^15,16 Around the same time, the WHO noted that transplantation, with its complex scientific as well as social, cultural, and ethical aspects, was “becoming a public health issue” requiring attention by the WHO, and sponsored 2 Task Force meetings in 1996 and 1997 to develop international guidance regarding transplantation safety, equitable access, and regulation.

The IXA and TTS’s motivation for establishing internationally accepted guidelines for xenotransplantation clinical trials was driven by concern for unique potential public health risks that might be anticipated when xenografted tissues are transplanted into immunosuppressed patients. As such in 1999, the WHO Transplantation Task Force recommended that WHO support and direct development of xenotransplantation policy.

Further interactions continued with many exchanges at various levels between IXA, TTS, and WHO to ensure that appropriate regulations were developed and continued worldwide.

During the WHO General Assembly in May 2004, the WHO adopted Resolution WHA57.18, which proposed that WHO Member States should not authorize xenotransplantation unless there was an effective system of control by national health authorities. WHO also encouraged Member States to establish standards of regulation and oversight of xenotransplantation.¹⁷ Moreover, WHO asked Member States to draw up an inventory of clinical trials of xenotransplantation taking place in their territory.

To this end, a panel of experts gathered by the WHO met in Geneva in 2005 and proposed to initiate an inventory on clinical xenotransplantation activities. This inventory was launched in 2006 and a first report summarized the period 1995–2010.² We present here the update of the inventory for the period 2010–2020. When compared with the first reported period (1995–2010, with 29 activities, mostly without governmental regulation), the recent number of clinical activities was reduced, but all were officially approved. Regarding safety issues, no serious complication or deaths were reported in the follow-up of these clinical trials. It is clear that prolonged follow-up will be necessary to allow larger clinical application.

Regarding efficacy, the transplantation of xenogeneic skin showed promising results in terms of wound healing when compared with human skin from a deceased donor. Furthermore, the transplantation of xenogeneic cornea showed functional grafts at 1 y in the majority of patients. The transplantation of porcine islets or neurogeneic cells did not clearly show consistent results and suggests that additional preclinical research is necessary to initiate new clinical trials.

Xenotransplantation represents an option for solving the major shortage of human organ donors; however, its safety must be secured before large clinical application can commence in earnest. Currently, small trials are ongoing around the world and all of the recent trials have been officially approved by national or local committees. This is in contrast to the previous reporting period (1995 to 2010), i the majority of activities were performed in countries without regulation regarding xenotransplantation.

Progress in preclinical models of pig organ and cell xenotransplantation has been so encouraging that several groups worldwide are taking steps to advance to initial clinical trials. Therefore, it becomes obvious that a new international registry should be launched to collect data on worldwide activities of xenotransplantation. In collaboration between WHO and Transplantation societies, the Global Observatory on Donation and Transplantation was started in 2008.¹⁸ This registry is archiving data on worldwide organ donation and allotransplantation and could be the platform for a transparent archiving of xenotransplantation activities. Similar to the initial IXA inventory, minimal data on porcine source animal and breeding, as well as recipient information on organ or cell transplant and immunosuppression used should be included. This information should be used to inform healthcare staff and the public with the objective of encouraging good practices based on internationally harmonized guidelines.