Slide 1: Extended Survival of 9- and 10-Gene Edited Pig Heart Xenografts
Extended Survival of 9 - and 10 - Gene Edited Pig Heart Xenografts with Ischemia Minimization and CD154 Costimulation Blockade – Based Immunosuppression June 4, 2024 Ɣ Amir Sanatkar MD. 1 Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA
Slide 2: Relevant Disclosures
Relevant Disclosures • R. Chaban was supported by the Benjamin Research Fellowship from the German Research Foundation (DFG) • I. Ileka is supported by T32 5T32 AI007529 - 24 • Gene edited pigs were provided by Revivicor and NSRRC (NIH grant U42OD011140) • Tonix Pharmaceuticals provided TNX - 1500*,
Slide 3: Background
Background • Gene - edited (GE) pigs for Xenotransplantation. – Removal of CHO antigen targets of preformed Ab • TKO (Gal - 1,3 - Gal, Neu5Gc, 4Gal) – Addition of human regulatory molecules • Complement: CD46, CD55, CD59 • Coagulation: TBM, EPCR, TFPI – Addition of human anti - inflammatory ‘tra
Slide 4: Methods
Methods • Current study: – 3 - , 9 - , or 10 - GE pig hearts – novel costimulation - based immunosuppressive (TONIX - 1500) – cold - perfused storage technique designed to minimize graft ischemia . • Eight baboon recipients received heterotopic heart transplants » 3 Reference pig hearts (National Sw
Slide 5: Preservation Methods: Steen Ischemia Minimization
Preservation Methods: Steen Ischemia Minimization 5 » battery - powered portable perfusion circuit » 4 o C Steen Solution buffered extracellular solution (laboratory - made) » Protocol 2 - hr perfusion » 240ml of washed human RBCs + 760 ml Steen solution » Aortic perfusion at 4 o C, 40 - 50 mmHg, im
Slide 6: Methods: Heterotopic Heart Transplantation
Methods: Heterotopic Heart Transplantation
Slide 7: Methods: Recipient Immunosuppressive Treatment Regimen
Methods: Recipient Immunosuppressive Treatment Regimen • Induction : o ATG o α CD20 • Day 0 : o TNF ( inh ) o IL - 6 ( inh ) o Thromboxane inhibitor (BIA) • Maintenance Therapy : o α CD154 (TNX - 1500) o MMF o Corticosteroids o IL - 6 ( inh )
Slide 8: Results: Xenograft survival
0 100 200 300 400 500 0 50 100 Survival post Heart Tx Days P r o b a b i l i t y o f S u r v i v a l 3G 9G 10G Results: Xenograft survival
Slide 9: Results: Summary
Results: Summary Final Biopsy Graft Survival (Days) Major complication Anticoagulation GE Animal ID Antibody mediated rejection 3 Graft rupture Heparin IV 3G B3022 Antibody mediated rejection 5 Graft rupture Heparin IV 3G B2922 No evidence of rejection 0 Refractory Ventricular fibrillation Heparin I
Slide 10: Results: Graft Survival, Function, and Morphology
Results: Graft Survival, Function, and Morphology
Slide 11: Results: CRP, IL-6
Results: CRP, IL - 6 *Dashed lined is the upper limit of the CRP assay *
Slide 12: Results: Clinical condition, cardiac injury
Results: Clinical condition, cardiac injury
Slide 13: Anti-donor antibody levels
Anti - donor antibody levels:
Slide 14: Results: Histology
A B2721 (9GE) D#50 B B2721 (9GE) D#50 C B2721 (9GE) D#275 D B2721 (9GE) D#275 Results: Histology
Slide 15: Results: Histology
E B7221 (10GE) D#50 F B7221 (10GE) D#50 G B7221 (10GE) D#113 H B7221 (10GE) D#113 Results: Histology
Slide 16: Results: Histology
Results: Histology | B2622 (10GE) D#120 J B2622 (10GE) D#120 K B3022 (3GE) D#3 L B3022 (3GE) D#3 sa: 32 ‘ S H ARVARD x ATC 2024 CENTER FOR TRANSPLANTATION SCIENCES
Slide 17: Conclusions
Conclusions • 9 - or 10 - GE pig hearts exhibit promising performance.(Compared to reference basic genetics) in a clinically applicable regimen • Peri - transplant myocardial injury and systemic inflammation occur consistently, However; recovery and survival can be achieved using Gene modifications
Slide 18: fs Revivicor
fs Revivicor e ( ) A UNITED THERAPEUTICS COMPANY TONIX PHARMACEUTICALS j National Swine Resource | | & Research Center & FS MASSACHUSETTS i) GENERAL HOSPITAL 3 HARVARD MEDICAL SCHOOL ATES