Heidi Reich1, Eleni Tseliou2, Geoffrey de Couto2, David Angert3, Jackelyn Valle2, Yuzu Kubota4, Daniel Luthringer3, James Mirocha5, Baiming Sun2, Rachel R Smith6, Linda Marbán7, Eduardo Marbán8. 1. Cedars-Sinai Heart Institute, Los Angeles, California, USA; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA. 2. Cedars-Sinai Heart Institute, Los Angeles, California, USA. 3. Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA. 4. Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA. 5. Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. 6. Capricor, Therapeutics, Inc., Beverly Hills, California, USA. 7. Cedars-Sinai Heart Institute, Los Angeles, California, USA; Capricor, Therapeutics, Inc., Beverly Hills, California, USA. 8. Cedars-Sinai Heart Institute, Los Angeles, California, USA. Electronic address: eduardo.marban@csmc.edu.
Abstract
BACKGROUND: A single dose of allogeneic cardiosphere-derived cells (CDCs) improves cardiac function and reduces scarring, and increases viable myocardium in the infarcted rat and pig heart without eliciting a detrimental immune response. Clinical trials using single doses of allogeneic human CDCs are underway. It is unknown whether repeat dosing confers additional benefit or if it elicits an immune response. METHODS: Wistar-Kyoto rats underwent coronary artery ligation and intramyocardial injection of CDCs, with a second thoracotomy and repeat CDC injection 3 weeks later. Treatment permutations included 2 doses of allogeneic Brown-Norway CDCs (n = 24), syngeneic Wistar-Kyoto CDCs (n = 24), xenogeneic human CDCs (n = 24) or saline (n = 8). Cardiac function was assessed by transthoracic echocardiography, infarct size and inflammatory infiltration by histology, and cellular and humoral immune responses by lymphocyte proliferation and alloantibody assays. RESULTS: Repeat dosing of allogeneic and syngeneic CDCs improved ejection fraction by 5.2% (95% CI 2.1 to 8.3) and 6.8% (95% CI 3.8 to 9.8) after the first dose, and by 3.4% (95% CI 0.1% to 6.8%) and 6.4% (95% CI 4.2% to 8.6%) after the second dose. Infarct size was equally reduced with repeat dosing of syngeneic and allogeneic CDCs relative to xenogeneic and control treatments (p < 0.0001). Significant rejection-like infiltrates were present only in the xenogeneic group; likewise, lymphocyte proliferation and antibody assays were positive in the xenogeneic and negative in syngeneic and allogeneic groups. CONCLUSIONS: Repeat dosing of allogeneic CDCs in immunocompetent rats is safe and effective, consistent with the known immunomodulatory and anti-inflammatory properties of CDCs. These findings motivate clinical testing of repeatedly dosed CDCs for chronic heart disease.
BACKGROUND: A single dose of allogeneic cardiosphere-derived cells (CDCs) improves cardiac function and reduces scarring, and increases viable myocardium in the infarctedrat and pig heart without eliciting a detrimental immune response. Clinical trials using single doses of allogeneic humanCDCs are underway. It is unknown whether repeat dosing confers additional benefit or if it elicits an immune response. METHODS: Wistar-Kyoto rats underwent coronary artery ligation and intramyocardial injection of CDCs, with a second thoracotomy and repeat CDC injection 3 weeks later. Treatment permutations included 2 doses of allogeneic Brown-Norway CDCs (n = 24), syngeneic Wistar-Kyoto CDCs (n = 24), xenogeneic humanCDCs (n = 24) or saline (n = 8). Cardiac function was assessed by transthoracic echocardiography, infarct size and inflammatory infiltration by histology, and cellular and humoral immune responses by lymphocyte proliferation and alloantibody assays. RESULTS: Repeat dosing of allogeneic and syngeneic CDCs improved ejection fraction by 5.2% (95% CI 2.1 to 8.3) and 6.8% (95% CI 3.8 to 9.8) after the first dose, and by 3.4% (95% CI 0.1% to 6.8%) and 6.4% (95% CI 4.2% to 8.6%) after the second dose. Infarct size was equally reduced with repeat dosing of syngeneic and allogeneic CDCs relative to xenogeneic and control treatments (p < 0.0001). Significant rejection-like infiltrates were present only in the xenogeneic group; likewise, lymphocyte proliferation and antibody assays were positive in the xenogeneic and negative in syngeneic and allogeneic groups. CONCLUSIONS: Repeat dosing of allogeneic CDCs in immunocompetent rats is safe and effective, consistent with the known immunomodulatory and anti-inflammatory properties of CDCs. These findings motivate clinical testing of repeatedly dosed CDCs for chronic heart disease.
Authors: Russell G Rogers; Mario Fournier; Lizbeth Sanchez; Ahmed G Ibrahim; Mark A Aminzadeh; Michael I Lewis; Eduardo Marbán Journal: JCI Insight Date: 2019-04-04
Authors: Makoto Natsumeda; Victoria Florea; Angela C Rieger; Bryon A Tompkins; Monisha N Banerjee; Samuel Golpanian; Julia Fritsch; Ana Marie Landin; Nilesh D Kashikar; Vasileios Karantalis; Viky Y Loescher; Kostas E Hatzistergos; Luiza Bagno; Cristina Sanina; Muzammil Mushtaq; Jose Rodriguez; Marcos Rosado; Ariel Wolf; Kevin Collon; Louis Vincent; Anthony J Kanelidis; Ivonne H Schulman; Raul Mitrani; Alan W Heldman; Wayne Balkan; Joshua M Hare Journal: J Am Coll Cardiol Date: 2017-11-14 Impact factor: 24.094
Authors: David J Polhemus; Rishi K Trivedi; Thomas E Sharp; Zhen Li; Traci T Goodchild; Amy Scarborough; Geoffrey de Couto; Eduardo Marbán; David J Lefer Journal: Basic Res Cardiol Date: 2019-01-17 Impact factor: 17.165
Authors: Dina Rady; Marwa M S Abbass; Aiah A El-Rashidy; Sara El Moshy; Israa Ahmed Radwan; Christof E Dörfer; Karim M Fawzy El-Sayed Journal: Stem Cells Int Date: 2020-08-11 Impact factor: 5.443
Authors: Mohammad R Ostovaneh; Raj R Makkar; Bharath Ambale-Venkatesh; Deborah Ascheim; Tarun Chakravarty; Timothy D Henry; Glen Kowalchuk; Frank V Aguirre; Dean J Kereiakes; Thomas J Povsic; Richard Schatz; Jay H Traverse; Janice Pogoda; Rachel D Smith; Linda Marbán; Eduardo Marbán; Joao A C Lima Journal: Open Heart Date: 2021-07