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The New England Journal of Medicine Jul 2022A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard...
A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).
Topics: Animals; Animals, Genetically Modified; Extracorporeal Membrane Oxygenation; Heart; Heart Transplantation; Heterografts; Humans; Immunosuppression Therapy; Swine; Transplantation, Heterologous
PubMed: 35731912
DOI: 10.1056/NEJMoa2201422 -
Nature Reviews. Nephrology Dec 2022A major limitation of organ allotransplantation is the insufficient supply of donor organs. Consequently, thousands of patients die every year while waiting for a... (Review)
Review
A major limitation of organ allotransplantation is the insufficient supply of donor organs. Consequently, thousands of patients die every year while waiting for a transplant. Progress in xenotransplantation that has permitted pig organ graft survivals of years in non-human primates has led to renewed excitement about the potential of this approach to alleviate the organ shortage. In 2022, the first pig-to-human heart transplant was performed on a compassionate use basis, and xenotransplantation experiments using pig kidneys in deceased human recipients provided encouraging data. Many advances in xenotransplantation have resulted from improvements in the ability to genetically modify pigs using CRISPR-Cas9 and other methodologies. Gene editing has the capacity to generate pig organs that more closely resemble those of humans and are hence more physiologically compatible and less prone to rejection. Despite such modifications, immune responses to xenografts remain powerful and multi-faceted, involving innate immune components that do not attack allografts. Thus, the induction of innate and adaptive immune tolerance to prevent rejection while preserving the capacity of the immune system to protect the recipient and the graft from infection is desirable to enable clinical xenotransplantation.
Topics: Humans; Animals; Swine; Transplantation, Heterologous; Graft Survival; Primates; Tissue and Organ Procurement; Transplants; Graft Rejection
PubMed: 36198911
DOI: 10.1038/s41581-022-00624-6 -
Journal of Translational Medicine May 2022The establishing of the first cancer models created a new perspective on the identification and evaluation of new anti-cancer therapies in preclinical studies.... (Review)
Review
The establishing of the first cancer models created a new perspective on the identification and evaluation of new anti-cancer therapies in preclinical studies. Patient-derived xenograft models are created by tumor tissue engraftment. These models accurately represent the biology and heterogeneity of different cancers and recapitulate tumor microenvironment. These features have made it a reliable model along with the development of humanized models. Therefore, they are used in many studies, such as the development of anti-cancer drugs, co-clinical trials, personalized medicine, immunotherapy, and PDX biobanks. This review summarizes patient-derived xenograft models development procedures, drug development applications in various cancers, challenges and limitations.
Topics: Animals; Disease Models, Animal; Heterografts; Humans; Neoplasms; Precision Medicine; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 35538576
DOI: 10.1186/s12967-022-03405-8 -
Frontiers in Immunology 2019The increasing life expectancy of humans has led to a growing numbers of patients with chronic diseases and end-stage organ failure. Transplantation is an effective... (Review)
Review
The increasing life expectancy of humans has led to a growing numbers of patients with chronic diseases and end-stage organ failure. Transplantation is an effective approach for the treatment of end-stage organ failure; however, the imbalance between organ supply and the demand for human organs is a bottleneck for clinical transplantation. Therefore, xenotransplantation might be a promising alternative approach to bridge the gap between the supply and demand of organs, tissues, and cells; however, immunological barriers are limiting factors in clinical xenotransplantation. Thanks to advances in gene-editing tools and immunosuppressive therapy as well as the prolonged xenograft survival time in pig-to-non-human primate models, clinical xenotransplantation has become more viable. In this review, we focus on the evolution and current status of xenotransplantation research, including our current understanding of the immunological mechanisms involved in xenograft rejection, genetically modified pigs used for xenotransplantation, and progress that has been made in developing pig-to-pig-to-non-human primate models. Three main types of rejection can occur after xenotransplantation, which we discuss in detail: (1) hyperacute xenograft rejection, (2) acute humoral xenograft rejection, and (3) acute cellular rejection. Furthermore, in studies on immunological rejection, genetically modified pigs have been generated to bridge cross-species molecular incompatibilities; in the last decade, most advances made in the field of xenotransplantation have resulted from the production of genetically engineered pigs; accordingly, we summarize the genetically modified pigs that are currently available for xenotransplantation. Next, we summarize the longest survival time of solid organs in preclinical models in recent years, including heart, liver, kidney, and lung xenotransplantation. Overall, we conclude that recent achievements and the accumulation of experience in xenotransplantation mean that the first-in-human clinical trial could be possible in the near future. Furthermore, we hope that xenotransplantation and various approaches will be able to collectively solve the problem of human organ shortage.
Topics: Animals; Animals, Genetically Modified; Biomarkers; Blood Coagulation Disorders; Disease Management; Gene Expression Regulation; Graft Rejection; Graft Survival; Haplorhini; Humans; Immunity, Cellular; Immunity, Humoral; Models, Animal; Species Specificity; Swine; Translational Research, Biomedical; Transplantation Immunology; Transplantation, Heterologous
PubMed: 32038617
DOI: 10.3389/fimmu.2019.03060 -
Transgenic Research Jun 2022To bridge the gap between organ demand and supply, xenotransplantation has long been considered as a realistic option for end-stage organ failure. Early this year this... (Review)
Review
To bridge the gap between organ demand and supply, xenotransplantation has long been considered as a realistic option for end-stage organ failure. Early this year this promise became reality for David Bennett Sr., the first patient whose own failing heart was replaced with a xeno-pig heart. To get here has been a rollercoaster ride of physiological hurdles seemingly impossible to overcome, technological breakthroughs and ethical and safety concerns. It started in 1984, with Stephanie Fae Beauclair, also known as baby Fae, receiving a baboon heart, which allowed her to survive for another 30 days. For ethical reasons primate work was soon abandoned in favour of the pig. But increased phylogenetic distance also brought with it an increased immunological incompatibility. It has been the development of ever more sophisticated genetic engineering tools, which brought down the physiological barriers, enabled humanisation of porcine organs and helped addressing safety concerns. This renewed the confidence in xenotransplantation, brought new funding opportunities and resulted finally in the first in human trial.
Topics: Animals; Genetic Engineering; Humans; Phylogeny; Primates; Swine; Transplantation, Heterologous
PubMed: 35545691
DOI: 10.1007/s11248-022-00306-w -
British Medical Bulletin Mar 2018There is a continuing worldwide shortage of organs from deceased human donors for transplantation into patients with end-stage organ failure. Genetically engineered pigs... (Review)
Review
INTRODUCTION
There is a continuing worldwide shortage of organs from deceased human donors for transplantation into patients with end-stage organ failure. Genetically engineered pigs could resolve this problem, and could also provide tissues and cells for the treatment of conditions such as diabetes, Parkinson's disease and corneal blindness.
SOURCES OF DATA
The current literature has been reviewed.
AREAS OF AGREEMENT
The pathobiologic barriers are now largely defined. Research progress has advanced through the increasing availability of genetically engineered pigs and novel immunosuppressive agents. Life-supporting pig kidneys and islets have functioned for months or years in nonhuman primates.
AREAS OF CONTROVERSY
The potential risk of transfer of a pig infectious microorganism to the recipient continues to be debated.
GROWING POINTS
Increased attention is being paid to selection of patients for initial clinical trials.
AREAS TIMELY FOR DEVELOPING RESEARCH
Most of the advances required to justify a clinical trial have now been met.
Topics: Animals; Animals, Genetically Modified; Graft Survival; Heterografts; Humans; Swine; Tissue and Organ Harvesting; Transplantation, Heterologous
PubMed: 29228112
DOI: 10.1093/bmb/ldx043 -
Cardiovascular Research Feb 2023For many patients with terminal/advanced cardiac failure, heart transplantation is the most effective, durable treatment option, and offers the best prospects for a high... (Review)
Review
For many patients with terminal/advanced cardiac failure, heart transplantation is the most effective, durable treatment option, and offers the best prospects for a high quality of life. The number of potentially life-saving donated human organs is far fewer than the population who could benefit from a new heart, resulting in increasing numbers of patients awaiting replacement of their failing heart, high waitlist mortality, and frequent reliance on interim mechanical support for many of those deemed among the best candidates but who are deteriorating as they wait. Currently, mechanical assist devices supporting left ventricular or biventricular heart function are the only alternative to heart transplant that is in clinical use. Unfortunately, the complication rate with mechanical assistance remains high despite advances in device design and patient selection and management, and the quality of life of the patients even with good outcomes is only moderately improved. Cardiac xenotransplantation from genetically multi-modified (GM) organ-source pigs is an emerging new option as demonstrated by the consistent long-term success of heterotopic (non-life-supporting) abdominal and life-supporting orthotopic porcine heart transplantation in baboons, and by a recent 'compassionate use' transplant of the heart from a GM pig with 10 modifications into a terminally ill patient who survived for 2 months. In this review, we discuss pig heart xenotransplantation as a concept, including pathobiological aspects related to immune rejection, coagulation dysregulation, and detrimental overgrowth of the heart, as well as GM strategies in pigs to prevent or minimize these problems. Additional topics discussed include relevant results of heterotopic and orthotopic heart transplantation experiments in the pig-to-baboon model, microbiological and virologic safety concepts, and efficacy requirements for initiating formal clinical trials. An adequate regulatory and ethical framework as well as stringent criteria for the selection of patients will be critical for the safe clinical development of cardiac xenotransplantation, which we expect will be clinically tested during the next few years.
Topics: Humans; Animals; Swine; Transplantation, Heterologous; Quality of Life; Heart Transplantation; Treatment Outcome; Graft Rejection; Animals, Genetically Modified
PubMed: 36461918
DOI: 10.1093/cvr/cvac180 -
Nature Protocols 2014Human endothelial cells (ECs) and pericytes are of great interest for research on vascular development and disease, as well as for future therapy. This protocol...
Human endothelial cells (ECs) and pericytes are of great interest for research on vascular development and disease, as well as for future therapy. This protocol describes the efficient generation of ECs and pericytes from human pluripotent stem cells (hPSCs) under defined conditions. Essential steps for hPSC culture, differentiation, isolation and functional characterization of ECs and pericytes are described. Substantial numbers of both cell types can be derived in only 2-3 weeks: this involves differentiation (10 d), isolation (1 d) and 4 or 10 d of expansion of ECs and pericytes, respectively. We also describe two assays for functional evaluation of hPSC-derived ECs: (i) primary vascular plexus formation upon coculture with hPSC-derived pericytes and (ii) incorporation in the vasculature of zebrafish xenografts in vivo. These assays can be used to test the quality and drug sensitivity of hPSC-derived ECs and model vascular diseases with patient-derived hPSCs.
Topics: Animals; Cell Culture Techniques; Cell Differentiation; Cell Proliferation; Endothelial Cells; Heterografts; Humans; Pericytes; Pluripotent Stem Cells; Zebrafish
PubMed: 24874816
DOI: 10.1038/nprot.2014.102 -
Acta Neuropathologica Dec 2020Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the...
Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.
Topics: Animals; Brain Neoplasms; Glioblastoma; Glioma; Heterografts; Humans; Mice; Neoplasm Recurrence, Local; Organoids; Precision Medicine; Rats; Temozolomide
PubMed: 33009951
DOI: 10.1007/s00401-020-02226-7 -
Current Opinion in Organ Transplantation Oct 2020To describe the most recent progress towards tolerance in xenotransplantation. (Review)
Review
PURPOSE OF REVIEW
To describe the most recent progress towards tolerance in xenotransplantation.
RECENT FINDINGS
Mixed chimerism and thymic transplantation have been used to promote tolerance in xenotransplantation models. Intra-bone bone marrow transplantation is a recent advance for mixed chimerism, which promotes longer lasting chimerism and early graft function of subsequent organ transplantation. The hybrid thymus, an advancement to the vascularized thymokidney and vascularized thymic lobe, is being developed to allow for both donor and recipient T-cell selection in the chimeric thymus, encouraging tolerance to self and donor while maintaining appropriate immune function. Regulatory T cells show promise to promote tolerance by suppressing effector T cells and by supporting mixed chimerism. Monoclonal antibodies such as anti-CD2 may promote tolerance through suppression of CD2+ effector and memory T cells whereas Tregs, which express lower numbers of CD2, are relatively spared and might be used to promote tolerance.
SUMMARY
These findings contribute major advances to tolerance in xenotransplantation. A combination of many of these mechanisms will likely be needed to have long-term tolerance maintained without the use of immunosuppression.
Topics: Animals; Chimerism; Immune Tolerance; Models, Animal; Transplantation Tolerance; Transplantation, Heterologous
PubMed: 32796179
DOI: 10.1097/MOT.0000000000000795