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Xenotransplantation Controversies 2019 Xenotransplantation Controversies 2019 Lawrence S.C. Czer, M.D. Medical Director, Heart Transplant Program Professor of Medicine Cedars-Sinai Smidt Heart Institute & UCLA Los Angeles, CA, USA (310) 423-3851 [email protected] Cedars-Sinai Smidt Heart Institute No disclosures Xenotransplantation Controversies 2019 • “Everything that can be invented has been invented.” • Attributed to Charles H. Duell, Commissioner of US Patent Office in 1899, in “The Book of Facts and Fallacies” by Chris Morgan and David Langford published in 1981. • Punch Magazine January 4, 1899: “The Coming Century.” Cedars-Sinai Smidt Heart Institute Heart Failure: Scope of Problem in US • Prevalence: 5.8 million • Incidence: 550,000 newly diagnosed each yr • Hospital Admissions per year: • >1,000,000 with primary diagnosis of heart failure • 3,000,000 with primary or secondary diagnosis of HF • 6.5 million hospital days each year • Post discharge mortality ~ 50% @ 5 yrs • Post discharge readmissions ~ 25% @ 1 mo, ~ 50% @ 6 mo • Office visits 15 million each yr • The estimated direct and indirect cost of HF in the U.S. for 2010 was $39.2 billion (more Medicare dollars than any other diagnosis) Georghiade Circulation 2005 AHA/ACC heart failure guidelines 3 AHA 2012 Heart Disease and Stroke Statistical Update Projected increase in direct and indirect costs for HF 2012-2030 4 Projected US prevalence of HF from 2012 to 2030 Clinical Course of Heart Failure Cedars-Sinai Smidt Heart Institute 5 Circulation 2012, 125:1928-1952 Survival after HF Hospitalization 6 Setoguchi et al. Am Heart J 2007 Survival according to HF stage Ammar KA et al. Circulation 2007;115:1563-1570 7 Adult and Pediatric Heart Transplants Number of Transplants by Year and Location 6000 Other 5500 North America 5000 Europe 4500 4000 3500 3000 2500 2000 Number of transplants 1500 1000 500 0 NOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry. As 2019 such, the presented data may not mirror the changes in the number of heart transplants performed worldwide. citation 9 Problems Inherent in Heart Transplantation With Allografts • Organ donor shortage. • “Selection” criteria. • Heart transplant for relatively few. • Waitlist mortality. • Worldwide geographical disparity, lack of access. • Extensive organizational infrastructure required. • Potential for voluntary or involuntary coercion in organ donation. • Exploitation of prisoners and vulnerable populations. • Transplant tourism. • Expense. 10 Durable Mechanical Circulatory Support – The Answer? 11 12 13 14 Total Artificial Heart Arabia F, et al. J Heart Lung Transplant 2018;37:1304–1312 15 16 Dangi et al. Cellular & Molecular Immunology 2019; 16: 334-342 CRISPR-Cas family • RNA-guided endonuclease defense system protecting bacteria & archaea from invading viruses & plasmids • CRISPR-Cas9 most widely studied (simple structure, high degree of specificity). • Three main components: • Endonuclease Cas9 protein • CRISPR RNA (crRNA) • Trans-activating crRNA (tracrRNA) • Activation of Cas9 induces cleavage of the target DNA sequence & generates a double-strand DNA break • DNA break repaired by nonhomologous end-joining (NHEJ) or homology-directed repair (HDR) with high degree of accuracy • Multiple gene modifications at different sites simultaneously Jinek et al. Science 2012; 337: 816-821. 17 Wiedenheft Sternberg Doudna. Nature 2012; 482: 331-338. Emerging New Technologies: CRISPR-Cas9 18 Dangi et al. Cellular & Molecular Immunology 2019; 16: 334-342 CRISPR-Cas9 Applications Deletion of Carbohydrate Xenoantigens • Carbohydrate xenoantigens responsible for hyperacute rejection • Preformed human natural antibodies against porcine carbohydrate xenoantigens activate complement, membrane attack complex. • Main carbohydrate xenoantigens on porcine cells: • α-1,3-galactose by α-1,3-galactosyl-transferase (GGTA1) • N-glycolylneuraminic acid by cytidine monophosphate-N- acetylneuraminic acid hydroxylase (CMAH) • Non-gal glycan by β-1,4-N-acetylgalactosaminyltransferase (B4GALNT2) • Single (SKO), double (DKO), or triple knock out (TKO) pigs can be produced by targeting of GGTA1/CMAH/B4GALNT2 genes. Dangi et al. Cellular & Molecular Immunology 2019; 16: 334-342 19 20 Kim H, et. al. Transplant Proceedings 2019; 45, 3085-3091. CRISPR-Cas9 Applications MHC class I deletion • Swine Leukocyte Antigen (SLA)-null pigs created by disruption of seven alleles of SLA genes to remove all MHC class I molecules. • Some anti-HLA antibodies in humans can cross-react with class I SLA’s. • Human T-cell receptors can bind directly to SLA complexes. • Thus, class I SLA deletion beneficial in xenotransplantation. Dangi et al. Cellular & Molecular Immunology 2019; 16: 334-342 21 22 CRISPR-Cas9 Applications Complement C3 deletion • Complement system activation leads to formation of membrane attack complex in hyperacute rejection and acute vascular rejection. • C3 knock out (C3KO) pigs produced, with undetectable plasma C3. • Complement regulatory protein CD46-expressing pigs combined with GGTA1 knockout, thrombomodulin transgene, and immunosuppression produced longest heterotopic cardiac xenograft survival (945 days) in primate model. Dangi et al. Cellular & Molecular Immunology 2019; 16: 334-342 23 24 CRISPR-Cas9 Applications Inactivation of PERVs • Porcine endogenous retroviruses (PERVs) found in pig genome. • PERVs released from pig cells remain active in vivo. • PERVs can infect human cells in vitro • Pigs with 100% inactivated PERVs have been produced using CRISPR-Cas9. Dangi et al. Cellular & Molecular Immunology 2019; 16: 334-342 25 Niu D, et al. Science 2017 Aug 10 26 27 Kolata New York Times 2017 Aug 10 28 29 Xenotransplantation Controversies 2019 Xenotransplantation is the future of transplantation … and always will be? Norman Shumway MD Cedars-Sinai Smidt Heart Institute 30 Cedars-Sinai Smidt Heart Institute 31 Cedars-Sinai Smidt Heart Institute 32 33 34 .
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