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Pancreas and Islet Abstract Session

Sunday September 13, 2020 - 23:30 to 00:15

Room: Channel 9

213.1 A pilot clinical trial outcome of biosafety system evaluation for PERV-C free porcine islet xenotransplantation based on principle of WHO “Changsha Communique”

Wei Wang, People's Republic of China

Director of Department of Radiology
The Third Xiangya Hospital

Abstract

A pilot clinical trial outcome of biosafety system evaluation for PERV-C free porcine islet xenotransplantation based on principle of WHO “Changsha Communique”

Xiaoqian Ma1, Zhaohui Mo2, Yicong Chen3,4, Pengfei Rong1, Shengwang Zhang1, Juan Zhang1, Qiong Dong1, Cejun Yang1, Min Yang1, Guangqian Duan4, Minhua Luo5, Jie Cui3,4, Wei Wang1.

1The Institute for Cell Transplantation and Gene Therapy, The Third Hospital of Central South University, Changsha, People's Republic of China; 2Department of Endocrinology, The Third Hospital of Central South University, Changsha, People's Republic of China; 3CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People's Republic of China; 4Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, People's Republic of China; 5State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Tech, Wuhan Institute of Virology, Wuhan, People's Republic of China

Background: Xenotransplantation using porcine cells, tissues or organs is a promising method to alleviate the shortage of donated cadaveric human organs. Cross-species transmission of an infectious agent from the pig graft to the recipient, hepatic impact caused by an instant blood-mediated reaction, chronic over-immunosuppression and long-term potential infectious risk are the main concerns regarding xenotransplantation. Therefore, we designed a clinical trial to evaluate a biosafety system based on the principle of Changsha Communique for porcine islet xenotransplantation.
Methods: Based on current WHO guidelines and the existing pathogen list for designated pathogen-free (DPF) animals, we designed our updated DPF pathogen screening list. We had selectively inbred a Xiang pig herd for 12 years and confirmed their PERV-C free status and, most recently, their DPF status (Xeno-1). We here in report a clinical trial of ten adult patients (9 M:1 F) with type 1 diabetes who received DPF porcine islet xenotransplantation via the portal vein. Clinically accepted immunosuppressant protocol, tacrolimus, MMF, beletacept and autologous Tregs, were used for the recipients. The recipients were observed for follow-up biosafety evaluations such as infectious signs, microbiological detection, liver function, immunocytes and cytokines as the time schedule post-Tx. The recipients and their spouse were also examined the transmission of porcine endogenous retroviruses (PERV) and the micro-chimerism using PCR and cross-species infection monitoring.  
Results: PERV-C negative DPF donor piglets were certified in China by CFDA. All recipients and their spouse were minimal 1 year monitoring and up to 5 years. No cross-species pathogen infections and no PERV transmission were observed, and no severe transplant-related side effects were observed. Mild liver function damage was found post transplantation, but recover to normal within 28 days. We did not negatively alter the cytokine and immune responses in patients at 12 months’ post-islet xenotransplantation monitoring. The metabolic outcome improved, and hypoglycemic episodes decreased in all recipients. The exogenous insulin requirement decreased by an average of 45%, and the HbA1c decreased by 22.5% in recipients who received 11,400 ± 1828 IEQ/kg (n=4) at one year post transplantation.
Conclusion: This first-in-the-world pilot clinical trial for xenotransplantation biosafety system evaluation of fresh neonatal porcine islets demonstrates that validated DPF PERV-C-free pigs are safe from biohazard risks and transmission and are a valuable donor source of tissue for xenotransplantation. Our data demonstrate that this therapy is safe and efficacious, and these findings provide an important basis for future xenotransplantation studies.

This study was supported by the National Grant Program on Key Infectious Disease (2018ZX10301101-003), National Natural Science Foundation of China (Grant No. NSFC 81671752, 31671324, 31970176; Grant No. 2018SK1020). J.C is supported by CAS Pioneer Hundred Talents Program..

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