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Current Status of Xenotransplantation

Charleston 2009 Richard N. Pierson III, MD Immediate Past-President, IXA Professor of Surgery, U MD. Current Status of Xenotransplantation. Charleston 2009. Current science: What is holding us back? Organ xenografts Islets Regulatory progress: Where are we? Changsha, Islets, and beyond

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Current Status of Xenotransplantation

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  1. Charleston 2009Richard N. Pierson III, MDImmediate Past-President, IXAProfessor of Surgery, U MD Current Status of Xenotransplantation

  2. Charleston 2009 • Current science: What is holding us back? • Organ xenografts • Islets • Regulatory progress: Where are we? • Changsha, Islets, and beyond • A view forward

  3. Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Hyperacute Rejection C Human Blood “Natural” Anti-Gal IgM IgG C C C C C C C C Injured Pig Endothelial Cell Other Pig Proteins Gal 1,3 aGal sugars

  4. Two Key Pig Modifications Together Human Blood Anti-Pig IgM IgG “Natural” IgM IgG Y Y Y C Y Y Y Y Y C Y C Y Y Y Y Y Y Y Y C Y Y Y C Y Y Y Y Y Y CRP Y CRP Y CRP CRP GalTKO+CPRP TgPig Cell Other Pig Proteins Gal 1,3 aGal sugars

  5. GalTKO and/or hCRP organs in non-human primates • Early graft failure (EGF) unusual - with one modification: ~0-40% - with two modifications: <10% • Where are we today in preclinical models? • Heart: up to 6 month survival, but TM limiting • Kidney: up to 3 month survival, Rx complic. limiting • Liver: up to 7 days, thrombocytopenia limiting • Islets: over one year, clinically acceptable Rx needed

  6. Thrombotic Microangiopathy Caused by anti-pig antibody? Complement? Coagulation pathway activation?

  7. GalTKO and/or hCRP organs in non-human primates • Multiply modified pigs • GalTKO, hCPRP, coag regulator, immunomodulator • Where are we today in preclinical models? • Heart: elicited Ab vs thrombodysregulation • Kidney: (elicited Ab vs thrombodysregulation) • Liver: prevent thrombocytopenia • CD47-SIRPa (Wang/Yang, Venice 2009: IXA-O-12.6) • aGP1B/ vWF (Deckmyn, Venice 2009: IXA-O-6.2) • Islets: islet modification, anti-CD40 Rx

  8. immuno barrier xeno viruses fear factor

  9. Transmission of xenogeneic pathogens • Extensive studies of xenogeneic pathogens have furthered understanding of risks • Transplantation of pig tissues to humans and primates has not yet resulted in viral infection, even with immunosuppression • It seems reasonable to initiate carefully monitored clinical trials when efficacy likely J. Fishman, Xenotransplantation 2009

  10. “Xenonauts”: When to Launch? • International regulatory guidelines (Changsha) • Monitoring of recipient and close contacts • Archive cells and serum • Ethical consent • Correct patient • No better options • Scientific basis secure • Likely to succeed • Likely to be safe • Public education, consultation

  11. When to proceed: Regulatory National regulatory body approval Hospital IRB approval • Published IXA guidelines • Address local concerns Monitoring, oversight • Each jurisdiction (country) must decide who will do this • Registry (WHO) • Archiving (FDA-equivalent) Crucial step: international consensus Changsha Communique (2008) WHA action ~2011 IXA IsletConsensus Statement (2009) Ongoing comment process in Xenotransplantation Expert advice ad hoc to review proposed exceptions

  12. “Xenotransplantation is the future of transplantation….. and always will be” Sir Roy Calne/ Norman Shumway

  13. The future The history tells us that procedures • that were inconceivable yesterday, • and are barely achievable today, • often become routine of tomorrow. • Thomas E. Starzl, 1982

  14. Charleston 2009 What do you think?

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