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Xeno Shark Tank Session “We're Close but There Are a Few Issues to Work Out”

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Xeno Shark Tank Session “We’re Close but there are a few Issues to Work Out” Andrew Adams, MD, PhD Emory University Disclosure I have no relevant disclosures. CEOT 2018- Xeno Shark Tank “Are We Ready to Take the Plunge?” Xenotransplantation • Organ Shortage is the #1 Issue in Transplantation • Optimization of Donation will never fully answer the problem • Xenotransplantation has the potential to answer the organ shortage dilemma • Genetic Engineering- New Technologies have opened new possibilities • Recent Outcomes in Preclinical Models are Promising but are we ready to try it in patients? In order to see where we’re going, it is important to remember where we’ve been Early Attempts at Clinical Xenotransplantation . Early 1960’s limited options for pts with ESRD . Deceased donor kidney transplantation infancy . 23 y/o school teacher with renal failure . chimpanzee to human kidney transplant . functioned for 9 months . 5 additional xenotransplants (8-63 days) . All died of infections . Additional heart and liver xenografts Early Attempts at Clinical Xenotransplantation Reemtsma Liver Xenotransplantation Leonard Bailey Xeno Donors . Non-human primates – ethical concerns – infectious risks – limited numbers/endangered status – concordant . Pigs – ethically acceptable, food source – easier to breed large litters – similar organ size for adults The Emory – Discordant immunologic barrier Transplant Center Challenges with Xenotransplantation . Concordant vs Discordant – distinct carbohydrate expression- a-Gal Carbohydrate xenoantigens are major barrier to success • Most pig cells express galactose-α1,3-galactose (gal) on cellular surface, terminal carbohydrate group on glycoproteins and glycolipids • Produced by α-1,3-galactosyltransferase • Gal expression lost in humans and NHP through evolution • Coding region contains genetic mutation • Humans and NHP have natural pre-formed antibodies against gal • Develop through exposure to gut flora expressing gal The Emory Transplant Center Knock-out Pigs as Donors • a-Gal enzyme knocked out • prolonged survival of organs from minutes to days • homologous recombination, very inefficient, breeding, prolonged process (yrs) Large Animal Cloning The Emory Transplant Center CRISPR-Cas9 Xenotransplantation: Improving Outcomes anti-CD40 Heterotopic heart- almost 1000 days Orthotopic heart- <90 days Xeno Liver Transplantation Pre-formed Antibody Rejection Humans and Old World primates have natural pre-formed antibodies against Gal and other non-Gal xenoantigens Gal Gal Gal Gal Gal Gal Complement Cascade Hyperacute Rejection Porcine Donor Modifications Gal Total Knockout (GGTKO) Porcine Donor • Gal knockout removes major xenoantigen from porcine xenograft • Minor Gal and non-Gal proteins may still exist Gal Gal Gal Gal Gal Gal hDAF Transgenic Donor • Prevents C3 convertase and subsequent formation of the Complement Cascade membrane attack complex (MAC) Accelerated Rejection Pre-Transplant Screening for Minor, Non-Gal Antibodies GGTKO porcine donors still have minor, non-Gal antigens present on the surface of xenografts Gal Gal Gal Gal Gal Gal Complement Cascade Accelerated Rejection low pre-transplant anti-pig Ab selected • Pre-transplant crossmatch was performed with potential recipient rhesus macaques. • Serum was analyzed for anti-pig antibodies. • Animals with the lowest and highest antibody titers were selected for transplant. GGTKO/hDAF Porcine PBMC + Rhesus macaque serum Translation to a Preclinical Nonhuman Primate Model Genetically Nephrectomized modified pig Rhesus Macaque Vascular Anastomoses Completed Clamp released Pre-perfusion Perfused porcine kidney Low anti-pig antibody titers are associated with prolonged survival 100 Low titer High titer l a v i v r u s MST 160 days t 50 n e c Interstitial hemorrhage, edema r e P MST 6 days 0 0 100 200 300 Post-transplant Days Maximal Survival Time 0 50 100 150 200 250 300 350 400 450 500 Post-Transplant Day Previously Reported in Literature Pig Kidney to Nonhuman Primate d-3 d0 4 7 14 21 28 42 56 70 84 112 140 168 αCD4 αCD8 MMF 15 BID Steroid 12 IV 20 SQ 8 SQ 3.2 SQ 1.2 SQ daily anti-CD154 Weekly Every other week Pig-to-Primate Renal Xenotransplant Survival NHP Survival Times: 18, 160, 310, 406 MST: 235 Maximal Survival Time 0 50 100 150 200 250 300 350 400 450 500 Post-Transplant Day Reported In Literature T Cells in the Xenograft at Rejection • T Cells reconstitute on Post-Transplant Day 50. • Are CD4 or CD8 T Cells more importantT Cell in T Cell T CellT Cell T Cell causing xenograft rejection? T Cell T Cell T Cell T Cell T CellT Cell T Cell T Cell Graft-Infiltrating Cells at the time of Rejection Allograft Xenograft There are more CD4+ cells in the xenograft at the time of rejection. CD4+ CD8+ CD4+ CD8+ Hypothesis: Depletion of αCD4 is necessary for long-term xenograft survival in a pig-to-primate translational model of renal xenotransplant Mycophenolate Mofetil Solumedrol CoB Rhesus Macaque (n=3) Genetically Mycophenolate Mofetil modified pig Solumedrol CoB Rhesus Macaque (n=3) d0 4 7 14 21 28 42 56 70 84 112 140 168 Mycophenolate Mofetil mg/kg 15 BID Solumedrol mg 12 IV 20 SQ 8 SQ 3.2 SQ 1.2 SQ daily CoB Weekly Every other week Survival Benefit αCD4 versus αCD8 depletion NHP Survival Times: αCD4 + CoB: >70, 414, 499 MST: 414 αCD8 + CoB: 6, 6, 15 MST: 6 Maximal Survival Time 0 50 100 150 200 250 300 350 400 450 500 Post-Transplant Day Reported In Literature Immunologic Barriers • To date all successful regimens have included either anti- CD40 or anti-CD154 • Will similar results be achieved with other reagents? • Can we use standard immunosuppression? What Genes Do We Need? Regulation of Complement Coagulation Cascade -CD46-membrane cofactor protein -human Von Willebrand Factor (hVWF) -CD55- decay accelerating factor -human Thrombomodulin CD59- protectin -Endothelial protein C receptor (hEPCR) -human CD39 Deletion or Suppression of Gal or Human tissue factor pathway inhibitor nonGal antigens -Gal KO Anti-inflammatory -CMAH KO -Heme Oxygenase 1 (HO-1) -b4Gal KO -human CD47 -Human A20 Immune Response Genes -HLA-E/G -Human Fas (CD95L) -CTLA-4 -PD-L1 -SLA I/II KO -CIITA-DN Physiologic Considerations • Pig heart – Cardiac output, systolic volume, mean BP, HR, and blood flow are almost identical to human heart – Differences in heart valves- unknown impact long term – ? Increased arrhythmogenicity • Pig Kidney – Anatomically similar – Maximum concentration capacity and GFR are similar to humans – Serum electolytes, BUN, and Cr are similar to human – Electrolyte imbalances have largely been ignored Does Size Matter? Physiologic Considerations • Will pig hormones function properly? – Erythropoietin, need to replace with hEPO – Ca/Phos metabolism/ PTH axis – Renin/Angiotensin • Will the pig kidney respond to current medications? Physiologic Considerations • Pig Liver – Anatomically slightly different – LFTs slightly higher in pigs – Consumptive thrombocytpenia • May be mitigated by administration of human clotting factors Infectious Barriers • PERV- porcine endogenous retroviruses – Unclear if they can infect human tissue or if they represent an actual problem • Development of PERV KO pig Infectious Barriers • PERV- porcine endogenous retroviruses – Unclear if they can infect human tissue or if they represent an actual problem • Development of PERV KO pig – Will it be necessary to use this background in the first clinical trials • Other pathogens – HEV, porcine CMV, etc Blastocyst Chimera Conclusion • “We should solve the problem of organ transplantation by using heterografts (xenografts) one day if we try hard enough, and maybe in less than 15 years.” Sir Peter Medawar 1969 • “Xenotransplantation is just around the corner, but it may be a very long corner” Sir Roy Calne 1995 • “Xenotransplantation is the future of transplantation and always will be” Norman Shumway • "In investing, what is comfortable is rarely profitable." - Robert Arnott Emory Transplant Center UAB Transplant Mandy Ford Joe Tector Chris Larsen Matt Tector Tom Pearson Ken Newell Yerkes/DAR Brad Farris Elizabeth Strobert Joe Jenkins Laura Higginbotham Joyce Cohen Steven Kim Paul Johnson Dave Mathews NSRRC Cindy Breeden Randy Prather Ying Dong Kevin Wells Allison Stephenson Eric Walters Taylor Deane Support NIH RO1 AI126322 NHP Reagent Resource NIH U19 AI051731 Keith Reimann Carlos and Marguerite Mason Trust .
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