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https://www.readbyqxmd.com/read/29777358/generation-of-genetically-engineered-animals-using-engineered-endonucleases
#1
REVIEW
Jong Geol Lee, Young Hoon Sung, In-Jeoung Baek
The key to successful drug discovery and development is to find the most suitable animal model of human diseases for the preclinical studies. The recent emergence of engineered endonucleases is allowing for efficient and precise genome editing, which can be used to develop potentially useful animal models for human diseases. In particular, zinc finger nucleases, transcription activator-like effector nucleases, and the clustered regularly interspaced short palindromic repeat systems are revolutionizing the generation of diverse genetically-engineered experimental animals including mice, rats, rabbits, dogs, pigs, and even non-human primates that are commonly used for preclinical studies of the drug discovery...
May 17, 2018: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/29731087/seven-years-of-experiences-of-preclinical-experiments-of-xeno-heart-transplantation-of-pig-to-non-human-primate-cynomolgus-monkey
#2
S J Lee, J S Kim, H K Chee, I J Yun, K S Park, H S Yang, J H Park
BACKGROUND: The absolute shortage of donors compared with patients requiring transplantation is currently an unsolved problem, and the only possible solution may be xenotransplantation. To establish a successful clinical trial, a preclinical study using nonhuman primates is essential. Starting in November 2011, our team initiated heterotopic abdominal heart xenotransplantation, the first in the Republic of Korea. We present here the initial 7-year results. METHODS: A total of 22 xenotransplantation procedures have been performed since 2011...
May 2018: Transplantation Proceedings
https://www.readbyqxmd.com/read/29609635/why-was-perv-not-transmitted-during-preclinical-and-clinical-xenotransplantation-trials-and-after-inoculation-of-animals
#3
REVIEW
Joachim Denner
Porcine endogenous retroviruses (PERVs) are present in the genome of all pigs, they infect certain human cells and therefore pose a special risk for xenotransplantation using pig cells, tissues and organs. Xenotransplantation is being developed in order to alleviate the reduced availability of human organs. Despite the fact that PERVs are able to infect certain human cells and cells from other species, transmission of PERVs has not been observed when animals (including non-human primates) were inoculated with PERV preparations or during preclinical xenotransplantations...
April 2, 2018: Retrovirology
https://www.readbyqxmd.com/read/29604134/b4galnt2-and-xenotransplantation-a-newly-appreciated-xenogeneic-antigen
#4
REVIEW
Guerard Byrne, Saadullah Ahmad-Villiers, Zeji Du, Christopher McGregor
Analysis of non-Gal antibody induced after pig-to-baboon cardiac xenotransplantation identified the glycan produced by porcine beta-1,4-N-acetyl-galactosaminyltransferase 2 (B4GALNT2) as an immunogenic xenotransplantation antigen. The porcine B4GALNT2 enzyme is homologous to the human enzyme, which synthesizes the human SDa blood group antigen. Most humans produce low levels of anti-SDa IgM which polyagglutinates red blood cells from rare individuals with high levels of SDa expression. The SDa glycan is also present on GM2 gangliosides...
March 31, 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29602717/skin-xenotransplantation-historical-review-and-clinical-potential
#5
REVIEW
Takayuki Yamamoto, Hayato Iwase, Timothy W King, Hidetaka Hara, David K C Cooper
Half a million patients in the USA alone require treatment for burns annually. Following an extensive burn, it may not be possible to provide sufficient autografts in a single setting. Pig skin xenografts may provide temporary coverage. However, preformed xenoreactive antibodies in the human recipient activate complement, and thus result in rapid rejection of the graft. Because burn patients usually have some degree of immune dysfunction and are therefore at increased risk of infection, immunosuppressive therapy is undesirable...
March 27, 2018: Burns: Journal of the International Society for Burn Injuries
https://www.readbyqxmd.com/read/29582477/immune-molecular-profiling-of-whole-blood-drawn-from-a-non-human-primate-cardiac-xenograft-model-treated-with-anti-cd154-monoclonal-antibodies
#6
Sun A Ock, Keon Bong Oh, Seongsoo Hwang, Ik Jin Yun, Curie Ahn, Hyun Ken Chee, Hwajung Kim, Imran Ullah, Gi-Sun Im, Eung Woo Park
Most studies of xenografts have been carried out with complex immunosuppressive regimens to prevent immune rejection; however, such treatments may be fatal owing to unknown causes. Here, we performed immune molecular profiling following anti-CD154 monoclonal antibody (mAb) treatment in heterotopic abdominal cardiac xenografts from α-1,3-galactosyltransferase-knockout pigs into cynomolgus monkeys to elucidate the mechanisms mediating the undesirable fatal side effects of immunosuppressive agents. Blood samples were collected from healthy monkeys as control and then at 2 days after xenograft transplantation and just before humane euthanasia; 94 genes related to the immune system were analyzed...
March 26, 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29538262/overcoming-coagulation-dysregulation-in-pig-solid-organ-transplantation-in-nonhuman-primates-recent-progress
#7
Liaoran Wang, David K C Cooper, Lars Burdorf, Yi Wang, Hayato Iwase
There has recently been considerable progress in the results of pig organ transplantation in nonhuman primates (NHPs), largely associated with the availability of (i) pigs genetically-engineered to overcome coagulation dysregulation, and (ii) novel immunosuppressive agents. The barriers of thrombotic microangiopathy and/or consumptive coagulation were believed to be associated with (i) activation of the graft vascular endothelial cells (VECs) by a low level of anti-pig antibody binding and/or complement deposition and/or innate immune cell activity, and (ii) molecular incompatibilities between the NHP and pig coagulation-anticoagulation systems...
March 10, 2018: Transplantation
https://www.readbyqxmd.com/read/29537289/large-animal-models-of-stroke-and-traumatic-brain-injury-as-translational-tools
#8
Annabel Jain Sorby-Adams, Robert Vink, Renee Jade Turner
Acute central nervous system injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide. Studies in animal models have greatly enhanced our understanding of the complex pathophysiology that underlies TBI and stroke and enabled the pre-clinical screening of over 1000 novel therapeutic agents. Despite this, the translation of novel therapeutics from experimental models to clinical therapies has been extremely poor. One potential explanation for this poor clinical translation is the choice of experimental model, given that the majority of pre-clinical TBI and ischemic stroke studies have been conducted in small animals, such as rodents, which have small lissencephalic brains...
March 14, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29527745/galt-ko-pig-lungs-are-highly-susceptible-to-acute-vascular-rejection-in-baboons-which-may-be-mitigated-by-transgenic-expression-of-hcd47-on-porcine-blood-vessels
#9
Hironosuke Watanabe, Hisashi Sahara, Shunichiro Nomura, Tatsu Tanabe, Dilrukshi K Ekanayake-Alper, Lennan K Boyd, Nathan J Louras, Arsenoi Asfour, Makenzie A Danton, Siu-Hong Ho, Scott J Arn, Robert J Hawley, Akira Shimizu, Takeshi Nagayasu, David Ayares, Marc I Lorber, Megan Sykes, David H Sachs, Kazuhiko Yamada
BACKGROUND: Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5 days of histologically well-aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx). METHODS: Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n = 3), GalT-KO/humanCD47(hCD47)/hCD55 (n = 3), GalT-KO/hD47/hCD46 (n = 4), or GalT-KO/hCD39/hCD46/hCD55/TBM/EPCR (n = 1) swine...
March 12, 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29511143/development-and-characterization-of-a-guinea-pig-model-for-marburg-virus
#10
Gary Wong, Wen-Guang Cao, Shi-Hua He, Zi-Rui Zhang, Wen-Jun Zhu, Estella Moffat, Hideki Ebihara, Carissa Embury-Hyatt, Xiang-Guo Qiu
The Angolan strain of Marburg virus (MARV/Ang) can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice (MARV/Ang-MA), with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold-standard non-human primate (NHP) model...
January 18, 2018: Zoological Research
https://www.readbyqxmd.com/read/29511141/animal-models-for-filovirus-infections
#11
REVIEW
Vinayakumar Siragam, Gary Wong, Xiang-Guo Qiu
The family Filoviridae , which includes the genera Marburgvirus and Ebolavirus , contains some of the most pathogenic viruses in humans and non-human primates (NHPs), causing severe hemorrhagic fevers with high fatality rates. Small animal models against filoviruses using mice, guinea pigs, hamsters, and ferrets have been developed with the goal of screening candidate vaccines and antivirals, before testing in the gold standard NHP models. In this review, we summarize the different animal models used to understand filovirus pathogenesis, and discuss the advantages and disadvantages of each model with respect to filovirus disease research...
January 18, 2018: Zoological Research
https://www.readbyqxmd.com/read/29481836/nonclinical-evaluation-of-immunological-safety-in-g%C3%A3-ttingen-minipigs-the-confirm-initiative
#12
REVIEW
Jacques Descotes, Linda Allais, Philippe Ancian, Henrik Duelund Pedersen, Claire Friry-Santini, Antonio Iglesias, Tina Rubic-Schneider, Hollie Skaggs, Peter Vestbjerg
There is a growing need to consider non-rodent species for the immunological safety evaluation of drug candidates. The EU Framework-6 RETHINK Project demonstrated that the Göttingen Minipig is a relevant animal model for regulatory toxicology studies. Extensive knowledge on the immune system of domestic pigs is available and fewer differences from humans have been identified as compared to other species, such as mice or non-human primates. Minipig data are too scarce to allow for claiming full immunological comparability with domestic pigs...
April 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29463617/the-chlamydia-trachomatis-plasmid-and-ct135-virulence-factors-are-not-essential-for-genital-tract-infection-or-pathology-in-female-pig-tailed-macaques
#13
Dorothy L Patton, Yvonne C Sweeney, Audrey E Baldessari, Linda Cles, Laszlo Kari, Gail L Sturdevant, Chunfu Yang, Harlan D Caldwell
The Chlamydia trachomatis plasmid and inclusion membrane protein CT135 are virulence factors in the pathogenesis of murine female genital tract infection. To determine if these virulence factors play a similar role in female nonhuman primates, we infected pig-tailed macaques with the same C. trachomatis strains shown to be important in the murine model. Wild-type C. trachomatis and its isogenic mutant strain deficient in both plasmid and CT135 were used to infect macaques. Macaques were given primary and repeated cervicovaginal challenges with the wild-type and mutant strains...
May 2018: Infection and Immunity
https://www.readbyqxmd.com/read/29462643/pirouetting-pigs-a-large-non-primate-animal-model-based-on-unilateral-6-hydroxydopamine-lesioning-of-the-nigrostriatal-pathway
#14
Anette Bro Christensen, Jens Christian Hedemann Sørensen, Kåre Schmidt Ettrup, Dariusz Orlowski, Carsten Reidies Bjarkam
INTRODUCTION: The rotating 6-hydroxydopamine (6-OHDA) rat model has long been important when developing new treatment strategies for Parkinson's disease (PD). Similar non-human primate models have been developed for translational research purposes as large animal models are required by regulatory bodies as an intermediate "phase 0" trial step. However, experimental research in non-human primates encounters several economical and regulatory issues, which may be avoided by the alternative use of pigs as a large animal model for experimental brain research...
February 17, 2018: Brain Research Bulletin
https://www.readbyqxmd.com/read/29446180/pigs-expressing-the-human-inhibitory-ligand-pd-l1-cd-274-provide-a-new-source-of-xenogeneic-cells-and-tissues-with-low-immunogenic-properties
#15
Anna Buermann, Stoyan Petkov, Björn Petersen, Rabea Hein, Andrea Lucas-Hahn, Wiebke Baars, Antje Brinkmann, Heiner Niemann, Reinhard Schwinzer
BACKGROUND: The programmed cell death-1 (PD-1, CD279)/PD-Ligand1 (PD-L1, CD274) receptor system is crucial for controlling the balance between immune activation and induction of tolerance via generation of inhibitory signals. Expression of PD-L1 is associated with reduced immunogenicity and renders cells and tissues to an immune-privileged/tolerogenic state. METHODS: To apply this concept for clinical xenotransplantation, we generated human (h)PD-L1 transgenic pigs and characterized expression and biological function of the transgene at the cellular level...
February 15, 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29427404/interleukin-8-mediates-neutrophil-endothelial-interactions-in-pig-to-human-xenogeneic-models
#16
Beth M French, Selin Sendil, Krishna Mohan Sepuru, Jolene Ranek, Lars Burdorf, Donald Harris, Emily Redding, Xiangfei Cheng, Christopher T Laird, Yuming Zhao, Benjamin Cerel, Krishna Rajarathnam, Richard N Pierson, Agnes M Azimzadeh
BACKGROUND: Human neutrophils are sequestered by pig lung xenografts within minutes during ex vivo perfusion. This phenomenon is not prevented by pig genetic modifications that remove xeno-antigens or added human regulatory molecules intended to down-regulate activation of complement and coagulation pathways. This study investigated whether recipient and donor interleukin-8 (IL-8), a chemokine known to attract and activate neutrophils during inflammation, is elaborated in the context of xenogeneic injury, and whether human or pig IL-8 promote the adhesion of human neutrophils in in vitro xenograft models...
March 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29359356/the-value-of-glycated-albumin-for-the-prediction-of-graft-outcome-in-the-non-human-primate-porcine-islet-transplantation-model
#17
Hee Jung Kang, Haneulnari Lee, Eun Mi Park, Jong-Min Kim, Jun-Seop Shin, Chung-Gyu Park
BACKGROUND: The development of a precise and easy-to-use tool for monitoring islet graft function is important in clarifying the causes of graft loss, identifying appropriate therapy, and ensuring graft survival in the nonhuman primate (NHP) model of porcine islet transplantation (PITx). Glycated albumin (GA) is an indicator of intermediate-term changes in blood glucose control and is useful in clinical diabetes management. The validity of GA for monitoring graft function in NHP recipients of PITx was evaluated using a retrospective analysis of cohort samples...
March 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29350404/gastrointestinal-protists-and-helminths-of-habituated-agile-mangabeys-cercocebus-agilis-at-bai-hokou-central-african-republic
#18
Barbora Pafčo, Zuzana Tehlárová, Kateřina Jirků Pomajbíková, Angelique Todd, Hideo Hasegawa, Klára J Petrželková, David Modrý
Infectious diseases including those caused by parasites can be a major threat to the conservation of endangered species. There is thus a great need for studies describing parasite infections of these species in the wild. Here we present data on parasite diversity in an agile mangabey (Cercocebus agilis) group in Bai Hokou, Dzanga-Sangha Protected Areas (DSPA), Central African Republic. We coproscopically analyzed 140 mangabey fecal samples by concentration techniques (flotation and sedimentation). Agile mangabeys hosted a broad diversity of protistan parasites/commensals, namely amoebas (Entamoeba spp...
February 2018: American Journal of Primatology
https://www.readbyqxmd.com/read/29210476/delayed-revascularization-of-islets-after-transplantation-by-il-6-blockade-in-pig-to-non-human-primate-islet-xenotransplantation-model
#19
Byoung-Hoon Min, Jun-Seop Shin, Jong-Min Kim, Seong-Jun Kang, Hyun-Je Kim, Il-Hee Yoon, Su-Kyoung Park, Ji-Won Choi, Min-Suk Lee, Chung-Gyu Park
BACKGROUND: Pancreatic islet transplantation is currently proven as a promising treatment for type 1 diabetes patients with labile glycemic control and severe hypoglycemia unawareness. Upon islet transplantation, revascularization is essential for proper functioning of the transplanted islets. As IL-6 is important for endothelial cell survival and systemic inflammation related to xenograft, the effect of IL-6 receptor antagonist, tocilizumab, on revascularization of the transplanted islets was examined in pig to non-human primate islet xenotransplantation model...
January 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29210109/xenotransplantation-back-to-the-future
#20
REVIEW
Raphael P H Meier, Yannick D Muller, Alexandre Balaphas, Philippe Morel, Manuel Pascual, Jörg D Seebach, Leo H Buhler
The field of xenotransplantation has fluctuated between great optimism and doubts over the last 50 years. The initial clinical attempts were extremely ambitious but faced technical and ethical issues that prompted the research community to go back to preclinical studies. Important players left the field due to perceived xenozoonotic risks and the lack of progress in pig-to-nonhuman-primate transplant models. Initial apparently unsurmountable issues appear now to be possible to overcome due to progress of genetic engineering, allowing the generation of multiple-xenoantigen knockout pigs that express human transgenes and the genomewide inactivation of porcine endogenous retroviruses...
December 5, 2017: Transplant International: Official Journal of the European Society for Organ Transplantation
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