National production of genetically modified pigs for organ xenotransplantation in humans

• Grant number: 18/14275-5
• Support Opportunities: Research Grants - Research Partnership for Technological Innovation - PITE
• Start date: October 01, 2019
• End date: September 30, 2023
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Silvano Mario Attilio Raia
• Grantee: Silvano Mario Attilio Raia
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Company: EMS S/A
• CNAE: Atividades de atenção à saúde humana não especificadas anteriormente
• CNAE: Atividades de atenção à saúde humana não especificadas anteriormente
• City: São Paulo
• Pesquisadores principais: Jorge Elias Kalil Filho ; Maria Rita dos Santos e Passos Bueno ; Mayana Zatz
• Associated researchers: Ernesto da Silveira Goulart Guimarães ; Luciano Abreu Brito ; Luiz Carlos de Caires Júnior
• Associated research grant(s): 19/09467-5 - Multi-User Equipment approved in grant 18/14275-5: Micromanipulator - equipment for nuclear transfer, AP.EMU; 19/09474-1 - Multi-User Equipment approved in grant 18/14275-5: Nucleofector 4D - equipment used for genomic editing, AP.EMU
• Associated scholarship(s): 23/03544-3 - Oocyte maturation methods and in vitro culture of porcine embryos, BP.TT; 23/03029-1 - Immunophenotypic characterization and purification of genetically modified swine lines by FACS, BP.TT; 23/01859-7 - In vitro evaluation of the immunological activity of genetically modified swine strains., BP.TT; + associated scholarships 23/01768-1 - Immunophenotypic characterization and purification of genetically modified swine lines by FACS, BP.TT; 23/01766-9 - DNA sequencing and gene expression detection in genetically edited porcine cell lines, BP.TT; 23/02009-7 - Neonatal management of genetically modified pigs for organ donation, BP.TT; 23/01765-2 - Comparative Analysis of Wild-type and Edited Porcine Cells by Anti-HLA Antibody Binding and by Transcriptomics., BP.TT; 20/11523-8 - Establishment of porcine transgenic cell line with potential for immune escape forxenotransplantation in humans, BP.PD; 20/08726-4 - Computational comparative analysis of human and swine leukocyte antigens (HLA/SLA) and its implications in xenotransplantation, BP.PD - associated scholarships

Abstract

Motivated by the growing need for transplantation-available organs and the latest developments in genomic editing technologies such as the CRISPR-Cas9 system, significant progress in the efficiency and safety of xenotransplantation techniques has been achieved in the last two years. Genetically engineered pigs developed to prevent receptor hyperacute immune rejection have been successfully developed in other countries. However, the possibility of cross-infection of pathogens such as PERVs (porcine endogenous retrovirus) must be controlled before the starting of therapeutic trials in humans. This project proposes the innovative national production of genetically modified pigs where genes known as inducers of hyperacute rejection (GGTA1 / CMAH / ²4GalNT2) will be knocked out. Furthermore, the copies of the PERV pol gene will be inactivated from the porcine genomic DNA. To this end, this project associates geneticists, immunologists, surgeons and clinicians with known experience and credibility in their respective area of knowledge for the development of a national biotechnological based product. At the very end, we aim to provide the population in waiting list for transplants a viable alternative and definitive therapy, thus shortening the suffering of the patients and their families. Furthermore, besides technological aspects, the viability of xenotransplantation in Brazil will require great efforts to conciliate ethical, religious and legal aspects. On this respect, our previous experience as a pioneer of intervivos liver transplantation in the world in the 80s will be extremely valuable. (AU)