IXA Vanguard Committee
Focus on Seoul National University Xeno-Lab
Xenotransplantation Research at Seoul National University, South Korea
Team of Jaeseok Yang, MD, PhD and Curie Ahn, MD, PhD
Our research teams are housed in the Center for Medical Innovation at the Seoul National University Hospital and the Designed Animal & Transplantation Research Institute on Pyeongchang Campus of Seoul National University. Our teams have been generating transgenic pigs for xenotransplantation and performing xenotransplantation using mice and cynomolgus monkeys as recipients.
Our teams were initially interested in molecular interactions between human and pig molecules and followed cellular activation in both parts. We focused on the effect of human TNF-α (one of cytokines secreted by early activated human innate immune cells) and CD40L (one of the costimulatory molecules on activated T cells and platelet) on pig aortic endothelial cells (PAECs). With stimulation by these molecules, PAECs were activated, several chemokines such as IP-10 and RANTES were secreted, and some adhesion molecules including E-selectin and VCAM-1 were upregulated. In order to diminish the response, we selected human soluble TNFR1-IgG1 Fc fusion protein (hsTNFR1-Fc) and HO-1 as target molecules.
We worked with Dr. Byeong Chun Lee (Department of Theriogenology and Biotechnology, College of Veterinary Medicine, Seoul National University) to generate HO-1 transgenic pigs (2010), hsTNFR1-Fc transgenic pigs (2010), and hsTNFR1-Fc/HO-1 double transgenic pigs (2011) using bi-cistronic 2A peptide. We identified the expression of target genes in adult porcine islets from these transgenic pigs and evaluated the function of target genes using the pig-to-mouse islet xenotransplantation model. Survival of the islet xenograft was significantly prolonged in both the hsTNFR1-Fc and HO-1 groups compared with that in the wild type group.
We additionally tested the effect of target genes overexpression in adult porcine islets using humanized mice as recipients in a collaboration with Dr. Sung Joo Kim (Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine). The introduction of either gene or both genes into islets significantly prolonged islet xenograft survival by suppressing both apoptosis and inflammation.
Our collaboration group recently generated GTKO/hsTNFR1-Fc/HO-1 transgenic pigs and GTKO/CMAHKO/hsTNFR1-Fc/HO-1 transgenic pigs. We are considering islet xenotransplantation into a cyno-monkey using oxygen-generating scaffold, which can help increase islet viability and insulin secretion.
In collaboration with Dr. Ik Jin Yun (Department of Surgery, Konkuk University School of Medicine), we have performed pig-to-cyno monkey heart or kidney xenotransplantation. We used GTKO pigs or GTKO/CD46 transgenic pigs that have been provided by the National Institute of Animal Science of the Rural Development Administration. A heart from a GTKO/CD46 transgenic pig recently transplanted into a cyno-monkey functionally survived for more than fifty days. We are now thinking of generating multi-transgenic pigs equipped with genes to downregulate complement and coagulation responses based on our GTKO pigs.
IXA 2017 Congress
Important Announcement from the Congress and SPC Chairs:
As you know, the IXA 2017 Congress will be held this September in Baltimore, Maryland. The abstract deadline has passed on April 10. We are delighted to announce that over 165 abstracts have been received from 130 different first authors which exceeded our expectations. Many thanks for your abstract submissions! Reviewer and SPC decisions will be made over the coming weeks, and notification to corresponding authors regarding acceptances will be sent out around May 17.
Abstract submission will remain open for late-breaking abstracts until May 1. If you or your team has new data that is significant for the xenotransplantation community, please submit your work. These submissions through the IXA 2017 website will be evaluated by the Scientific Program Committee (SPC), and will be considered for oral and poster presentations.
Please remember to encourage your trainees, junior members, and anyone who is a resident of an economically emerging country to apply for one of the 10 travel awards, which are being supported by IXA and TTS by May 1. Priority will be given to applicants with first-authored oral or oral poster abstracts accepted for presentation at the meeting.
Thanks again for your enthusiastic response to our Call for Abstracts, and we look forward to welcoming you in Baltimore this September!
Richard N. Pierson III, Congress Chair
Agnès Azimzadeh, SPC Chair
We would like to share with you the key points of a discussion that took place between your IXA council and two FDA representatives in Boston during the 2016 American Transplant Congress.
As you all know, xenotransplantation research has made significant progress during the last couple of years in a variety of preclinical models. Consequently, we believe that one or more xeno-based treatment methods may soon make their way to the clinic. The IXA council therefore opened a dialogue with the FDA, offering to make them aware of your scientific progress, and to seek their advice regarding regulatory issues that may arise in the US, and in other jurisdictions, as xenotransplantation moves towards clinical trials.
This was only an information-sharing meeting. Specifically, the FDA representatives warned us in advance that they would be unable to officially consider any changes to current policy, or commit to specific plans with respect to reconsidering official guidance regarding regulation of xenotransplantation. Members of the IXA council explained the bases for our enthusiasm about the near-term future of xenotransplantation. We then brought up 3 specific concerns regarding existing FDA guidance on xenotransplantation. These issues were: 1) the risk that PERV will emerge as a human pathogen appears to be low, and deserves to be recalibrated in light of improving prospects for therapeutic efficacy of one or more xeno-based treatments; 2) the requirement to assure 50 years of secure archiving of donor and recipient materials represents a formidable and arguably extraordinary burden for a clinical trial sponsor; and 3) some ambiguity exists regarding how genetically engineered source pigs would be classified with respect to the regulatory approvals path.
FDA shares IXA’s core goal: to facilitate the transition of xenotransplantation to the clinic, as safely as possible, as soon as preclinical evidence supports doing so. The FDA representatives gave their personal, individual opinions about the significant progress toward preclinical benchmarks, and we discussed the current regulatory recommendations. Unofficially, the FDA representatives were interested in exploring further discussions between the xenotransplantation community and the FDA. Specifically, the FDA representatives recommended that IXA provide a summary of the current ‘state of the art’ in those candidate xeno applications which appear closest to clinical application. That information will be reviewed within the FDA as the basis for making a decision regarding further official discussions with IXA and other interested parties, and regarding a possible recommendation to FDA and HHS leadership regarding revisiting xenotransplantation regulatory guidance. IXA was asked to be prepared to participate in a series of mutual information-sharing workshops with FDA subject matter experts for the purpose of better understanding each other’s viewpoints. IXA Council intends to send pertinent documents soon to the FDA.
Overall it was a very useful meeting. FDA leadership is now engaged, and aware that xenotransplantation research appears to be progressing rapidly towards clinical trials. Our meeting paved the way for further discussions and workshops. Importantly, we expect that future official interactions with FDA will include public consultative sessions open to all xenotransplantation researchers, potential sponsors, and other interested parties, in accordance with US regulatory policies and procedures.
On behalf of the IXA council we thank you all for your excellent work that triggered this discussion with the FDA.
We are sad to announce the passing of a true pioneer, TTS PAst-President and Medawar Laureate, Thomas E. Starzl.Thomas E. Starzl (1926-2017).
More information can be found here.
Scientists at the Salk Institute have successfully created a human-pig chimera for the first time
Credit: Juan Carlos Izpisua Belmonte
The ongoing organ shortage crisis has fueled a lucrative black market that generates over US$1 billion in profits every year. 3D-printed organs, despite their promise, remain a lab experiment for now, and while scientists have been cultivating cells in Petri dishes, they have yet to figure out how to replicate nature's cocktail of life-giving signals. Enter a new medical breakthrough that could one day solve this problem by incubating human organs in pigs – but should we let animals pick up the slack for us in the first place?
Read more here.
Below is a list of the top 10 downloaded articles in 2016 in Xenotransplantation.
- Cooper, D. et al. The pathobiology of pig‐to‐primate xenotransplantation: a historical review.
- Petersen, B. et al. Efficient production of biallelic GGTA1 knockout pigs by cytoplasmic microinjection of CRISPR/Cas9 into zygotes.
- Hering, B. et al. First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Executive summary.
- Butter, J. et al. Silencing the porcine iGb3s gene does not affect Galα3Gal levels or measures of anticipated pig‐to‐human and pig‐to‐primate acute rejection.
- Buermann, A. et al. Inhibition of B‐cell activation and antibody production by triggering inhibitory signals via the PD‐1/PD‐ligand pathway
- Cozzi, E. et al. Molecular immunology profiles of monkeys following xenografting with the islets and heart of α‐1,3‐galactosyltransferase knockout pigs.
- Lee, W. et al. Initial in vitro studies on tissues and cells from GTKO/CD46/NeuGcKO pigs.
- Itoh, T. et al. Islet‐derived damage‐associated molecular pattern molecule contributes to immune responses following microencapsulated neonatal porcine islet xenotransplantation in mice
- Lee, W. et al. Human antibody recognition of xenogeneic antigens (NeuGc and Gal) on porcine heart valves: could genetically modified pig heart valves reduce structural valve deterioration?
- Mahou, R. et al. Contribution of polymeric materials to progress in xenotransplantation of microencapsulated cells: a review.