Mice with humanized-lungs and immune system - an idealized model for COVID-19 and other respiratory illness.

Lack of an appropriate animal model to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for COVID-19 pandemic disease, represents a significant hurdle in the process of understanding disease biology and evaluating therapeutic and preventive candidates. It is time for public health agencies to revisit regulation on transplantation of human pluripotent stem cells for the possibility of the development of a humanized mice model with a humanized lung.

Regulation of Clinical Xenotransplantation: A Reappraisal of the Legal, Ethical, and Social Aspects Involved.

Clinical trials of encapsulated pig islet transplantation are underway and are showing promising results. In addition, better immunosuppressant drug regimens and a wealth of new gene-edited pig varieties are raising new hopes in this field. Thus, consideration is also being given to the selection of patients for initial clinical trials of pig solid organ xenotransplantation. It seems likely that clinical trials of pig organ will be initiated within the next couple of years. For the moment, transplanting porcine islets to treat type 1 diabetes is generally viewed as the most likely to reach the clinical first. Further advances will hopefully make this approach a treatment choice for patients with this condition. Regulatory framework for this type of xenotransplantation is now available in several countries, and there is also a wider awareness of the importance of developing an internationally harmonized regulatory framework. For now, xenotransplantation is mainly conceived and regulated as a pharmaceutical product. The reframing of this emerging technology as cell therapy has redefined the normative landscape. Countries should be cautious about allowing xenotransplantation clinical trials to develop. But the original meaning of precaution, referred to safety measures in order to control risks of infection, is no longer seen as requiring restrictive limitations on fundamental rights. As with any new medicinal product, safety is certainly a crucial topic in research. Specific to xenotransplantation is the safety of porcine product. In this regard, regulatory frameworks should contain specific conditions about the safety of the source animals, of the xenotransplantation product, and of the manufacturing process. In turn, these frameworks should ensure that preclinical studies indicate safety and efficacy of the procedure and that risk management protocols are in place to identify, contain, and combat any outbreak of infection in a timely manner. The fragile balance between individual and collective rights and the tensions of globalization make necessary a coordinated international action to harmonize global practices in this field. Xenotransplantation clinical trials should be carried out in a context in which specific safety and ethical issues are addressed and in an environment in which specific practices that facilitate public engagement as a form of shared responsibility for regulatory decision-making are promoted as well.

Regulatory barriers to xenotransplantation.

PURPOSE OF REVIEW: There is a grave discordance between supply and demand for patients with failing organs largely due to an insufficient donor pool for transplantation. Xenotransplantation has been proposed as a solution to bridge this gap. RECENT FINDINGS: Recent success over the last decade in nonhuman primate models, due to emerging gene-editing technologies combined with novel immunosuppression regimens, has produced promising results in pancreatic islet cell, heart, lung, kidney and liver xenotransplantations. SUMMARY: As the prospect of xenotransplantation is realized, safety and ethical considerations have come to the forefront of discussion. The WHO and World Health Assembly have encouraged member states to form regulatory bodies to govern human xenotransplantation studies with the highest standards. Here, we summarize the current regulatory landscape governing preclinical advances toward the first human clinical trials.

Xenotransplantation in China: Present status.

The main obstacle to organ transplantation is the shortage of organs from deceased individuals. Especially in China, the ratio of patients on the waiting list versus the transplant recipients is 30:1. Therefore, there is an urgent need for organ donors. Genetically modified pig organs have proved to be a new source for xenotransplantation, and Chinese scientists have made considerable progress in this area during recent years. In this paper, we review four important aspects of the xenotransplantation field in China. First, a large variety of genetically modified pigs have been generated by Chinese scientists: all these genetically modified pigs and the purpose of these modifications will be summarized. Second, the preclinical research in pig-to-nonhuman primate xenotransplantation is outlined. The survival time and major biochemical parameters for the xenografts are summarized. Third, regarding the bench-to-bed approach, more suitable organs have been developed for xenotransplantation in humans, and in particular, pig islet transplantation into diabetic patients as well as pig-to-human cornea and skin transplantation. Fourth, we briefly address the regulations and prospects for recruiting xenotransplantation experts in China. Based on recent progress, we anticipate that genetically modified pigs will offer suitable organs for the treatment of end-stage organ diseases in humans in the near future. Given the recent influx of world-renowned scientists in xenotransplantation to China, our country will definitely become one of the major centers of xenotransplantation research and development in the world.

Progress in multiple genetically modified minipigs for xenotransplantation in China.

Pig-to-human organ transplantation provides an alternative for critical shortage of human organs worldwide. Genetically modified pigs are promising donors for xenotransplantation as they show many anatomical and physiological similarities to humans. However, immunological rejection including hyperacute rejection (HAR), acute humoral xenograft rejection (AHXR), immune cell-mediated rejection, and other barriers associated with xenotransplantation must be overcome with various strategies for the genetic modification of pigs. In this review, we summarize the outcomes of genetically modified and cloned pigs achieved by Chinese scientists to resolve the above-mentioned problems in xenotransplantation. It is now possible to knockout several porcine genes associated with the expression of sugar residues, antigens for (naturally) existing antibodies in humans, including GGTA1, CMAH, and ß4GalNT2, and thereby preventing the antigen-antibody response. Moreover, insertion of human complement- and coagulation-regulatory transgenes, such as CD46, CD55, CD59, and hTBM, can further overcome effects of the humoral immune response and coagulation dysfunction, while expression of regulatory factors of immune responses can inhibit the adaptive immune rejection. Furthermore, transgenic strategies have been developed by Chinese scientists to reduce the potential risk of infections by endogenous porcine retroviruses (PERVs). Breeding of multi-gene low-immunogenicity pigs in China is also presented in this review. Lastly, we will briefly mention the preclinical studies on pig-to-non-human primate xenotransplantation conducted in several centers in China.

Xenotransplantation in Asia.

The organ shortage crisis affects most of the world today. In Asia, rates of deceased organ donation are extremely low due to sociocultural factors. In this context, implementing new organ donation policies is not enough; xenotransplantation remains the most promising way to solve the organ crisis. Most of the early research on xenotransplantation was conducted in the US and Europe. Today, however, Asia has caught up on its Western counterparts partly due to the increasing demand for organ transplants. Given the growing influence of countries such as China, South Korea, and Japan in xenotransplantation, this article provides the reader with an essential global understanding of the scientific and ethical issues currently at stake. Furthermore, it sheds light on the beliefs and values that shape the response of the Asian public to both organ donation and xenotransplantation.

Promising potentials of Tibetan macaques in xenotransplantation.

Organ transplantation is a crucial medical procedure, as it is often the only treatment for patients suffering from end-stage organ failure. Unfortunately, the shortage of donor organs limits the number of patients whose lives can be saved. Carrying out research on xenotransplantation with the aim of eventually replacing human organ transplants with those of animals is very promising, as it could effectively bridge the shortfall in donor organs. Thanks to the success of cloned pigs and to the emergence of gene-editing techniques, genetically modified pigs have come to be considered ideal animal donors for human xenotransplantation and have been widely used in basic research. Such research focuses on pig-to-nonhuman primates transplantation, as the recipients are suitable for preclinical studies because both their genes and organ sizes are similar to those of humans. Chinese transplantation scientists have carried out several experiments on Tibetan macaques, including successful preclinical transplants of material from genetically modified pigs, as well as research on such topics as intraocular pressure, Parkinson's disease, advanced cancer, islet transplantation, and liver transplantation. This article reviews basic and applied research on Tibetan macaques in xenotransplantation, as well as the issues of immune rejection and ethical concerns. We aim to demonstrate the various advantages of Tibetan macaques as transplant recipients compared to other nonhuman primate species and to provide a perspective for the future establishment of Tibetan macaques as principal recipients in preclinical studies of xenotransplantation.

Update regarding xenotransplantation in Japan.

To overcome the donor shortage, a promising solution could be xenotransplantation. The pig is generally considered the most suitable donor species for xenotransplantation. A clinical xenotransplantation has not been conducted in Japan. However, many progresses have recently been made in this field. Japan has regulations for conducting cell xenotransplantation and guidelines to prevent zoonosis. Most Japanese patients and their family members have a positive opinion about islet xenotransplantation. A grant for clinical islet xenotransplantation research and development has been approved, and germ-free pigs have been developed. Further research may bring the successful application of xenotransplantation closer to reality.

Non-viral pathogens: Identification, relevance, and prevention for xenotransplantation.

BACKGROUND: For xenotransplantation, strategies to prevent transmission of microorganisms from the source animal to the human recipient must be closely coordinated since tissues and organs are classified as non-sterile. Strategies for international cooperation and coordination of xenogeneic infection / disease surveillance and response are available. METHODS: The regulatory frameworks and criteria on microbial safety as published by World Health Organization (WHO), European Pharmacopoeia (Ph. Eur.), European Medicines Agency (EMA) as well as U.S. Department of Health and Human Services (DHHS), Food and Drug Administration (FDA) and Center for Biologics Evaluation and Research (CBER), are outlined. RESULTS: Different sources of microbial germs are considered including potential infectious agents. Monitoring of livestock and testing of xenografts is accompanied by positive and negative controls to detect and to exclude tissue specific microorganisms such as bacteria. CONCLUSIONS: The criteria of microbial status to be considered for xenotransplants are summarized.

Porcine to Human Heart Transplantation: Is Clinical Application Now Appropriate?

Cardiac xenotransplantation (CXTx) is a promising solution to the chronic shortage of donor hearts. Recent advancements in immune suppression have greatly improved the survival of heterotopic CXTx, now extended beyond 2 years, and life-supporting kidney XTx. Advances in donor genetic modification (B4GALNT2 and CMAH mutations) with proven Gal-deficient donors expressing human complement regulatory protein(s) have also accelerated, reducing donor pig organ antigenicity. These advances can now be combined and tested in life-supporting orthotopic preclinical studies in nonhuman primates and immunologically appropriate models confirming their efficacy and safety for a clinical CXTx program. Preclinical studies should also allow for organ rejection to develop xenospecific assays and therapies to reverse rejection. The complexity of future clinical CXTx presents a substantial and unique set of regulatory challenges which must be addressed to avoid delay; however, dependent on these prospective life-supporting preclinical studies in NHPs, it appears that the scientific path forward is well defined and the era of clinical CXTx is approaching.

Aspectos jurídicos del xenotrasplante / No disponible

A través del presente trabajo se pretende contextualizar el xenotrasplante bajo el marco legislativo aplicable en la actualidad resaltando aquellos aspectos que no pueden regirse mediante la legislación vigente y valorando la necesidad de su actualización ante la aparición de nuevas opciones como el empleo de animales modificados genéticamente como fuente de obtención de órganos

This paper aims to contextualize xenotransplantation under the current legislative framework, thus presenting the base upon which this approach is regulated, emphasizing those aspects that cannot be governed by the applicable law and assessing the need for an update because of the emergence of new options such as the use of genetically modified animals as a source for organ procurement

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 1: update on national regulatory frameworks pertinent to clinical islet xenotransplantation.

Islet xenotransplantation represents an attractive solution to overcome the shortage of human islets for use in type 1 diabetes. The wide-scale application of clinical islet xenotransplantation, however, requires that such a procedure takes place in a specifically and tightly regulated environment. With a view to promoting the safe application of clinical islet xenotransplantation, a few years ago the International Xenotransplantation Association (IXA) published a Consensus Statement that outlined the key ethical and regulatory requirements to be satisfied before the initiation of xenotransplantation studies in diabetic patients. This earlier IXA Statement also documented a disparate regulatory landscape among different geographical areas. This situation clearly fell short of the 2004 World Health Assembly Resolution WHA57.18 that urged Member States "to cooperate in the formulation of recommendations and guidelines to harmonize global practices" to ensure the highest ethical and regulatory standards on a global scale. In this new IXA report, IXA members who are active in xenotransplantation research in their respective geographic areas herewith briefly describe changes in the regulatory frameworks that have taken place in the intervening period in the various geographic areas or countries. The key reassuring take-home message of the present report is that many countries have embraced the encouragement of the WHO to harmonize the procedures in a more global scale. Indeed, important regulatory changes have taken place or are in progress in several geographic areas that include Europe, Korea, Japan, and China. Such significant regulatory changes encompass the most diverse facets of the clinical application of xenotransplantation and comprise ethical aspects, source animals and product specifications, study supervision, sample archiving, patient follow-up and even insurance coverage in some legislations. All these measures are expected to provide a better care and protection of recipients of xenotransplants but also a higher safety profile to xenotransplantation procedures with an ultimate net gain in terms of international public health.