Stem cells Bosnia.br.. - Progenitor Cell Therapy, LLC

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Stem cells Bosnia.br.. - Progenitor Cell Therapy, LLC

  1. 1. 1 Stem Cells in cardiovascular diseases Arshed A. Quyyumi MD; FRCPArshed A. Quyyumi MD; FRCP Professor of MedicineProfessor of Medicine Division of CardiologyDivision of Cardiology Emory University School ofEmory University School of MedicineMedicine Atlanta, Georgia, USAAtlanta, Georgia, USA
  2. 2. Disclosure of Financial Relationships • Grant/research support: National Institutes of Health, American Heart Association Eli Lilly, Novartis, Pfizer, Amorcyte, Biomarin, Forest • Advisory Boards: Amorcyte, Endothelix, Novartis
  3. 3. Types of Stem Cells • Embryonic stem cells – Pluripotent • Fetal and adult stem cells (e.g. mesenchymal cells) – Multipotent; capable of producing a small range of differentiated cell lineages appropriate to their location • Adult progenitor cells (e.g. skeletal myoblasts and endothelial progenitor cells) – Unipotent; has the least differentiation potential • Induced pluripotent stem cells (IPS)
  4. 4. Adult Bone Marrow Stem Cell PlasticityAdult Bone Marrow Stem Cell Plasticity Endodermal Progenitor Cells Bone Marrow Stem Cells Ectodermal Progenitor Cells Mesodermal Progenitor Cells Neural cells Epidermal cells Hepatocytes Hematopoeitic cells Endothelial Progenitor Cells Myocytes (Skeletal) (Cardiac) Osteocytes, Chondrocytes Stromal or Mesenchymal MAPC Blood cells Resident stem cells: Heart, skeletal muscle, Adipose tissue, brain, Lung etc.
  5. 5. Rafii S & Lyden D Nature Medicine 9, 702 - 712 (2003) Cerdani DJ Nat Med 2004 Hypoxia HIF-1 SDF-1 CXCR4 Endothelial cells Smooth muscle cells VEG F PDGF
  6. 6. Human studies with cell therapy inHuman studies with cell therapy in cardiovascular diseasescardiovascular diseases  Cell types:Cell types:  Endothelial progenitor cellsEndothelial progenitor cells::  Bone marrow mononuclear cells,Bone marrow mononuclear cells,  Bone marrow endothelial progenitors eg. CD34+, CD133+ etcBone marrow endothelial progenitors eg. CD34+, CD133+ etc  Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion)  Cord bloodCord blood  Skeletal myoblastsSkeletal myoblasts  Mesenchymal stem cellsMesenchymal stem cells  Resident cardiac stem cellsResident cardiac stem cells  Adipose tissue progenitorsAdipose tissue progenitors  Disease states:Disease states:  Acute MI,Acute MI,  Heart failure with scar or hibernating myocardium,Heart failure with scar or hibernating myocardium,  Chronic ischemia not amenable to conventionalChronic ischemia not amenable to conventional revascularizationrevascularization
  7. 7. Delivery options for stem cellsDelivery options for stem cells  IntracoronaryIntracoronary Coronary sinusCoronary sinus  Direct myocardialDirect myocardial injection epicardial,injection epicardial, endocardial),endocardial),  IntravenousIntravenous  Bone marrowBone marrow mobilizationmobilization Delivery devices
  8. 8. Human studies with cell therapy inHuman studies with cell therapy in cardiovascular diseasescardiovascular diseases  Cell types:Cell types:  Endothelial progenitor cellsEndothelial progenitor cells::  Bone marrow mononuclear cells,Bone marrow mononuclear cells,  Bone marrow endothelial progenitors eg. CD34+, CD133+ etcBone marrow endothelial progenitors eg. CD34+, CD133+ etc  Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion)  Cord bloodCord blood  Skeletal myoblastsSkeletal myoblasts  Mesenchymal stem cellsMesenchymal stem cells  Resident cardiac stem cellsResident cardiac stem cells  Disease states:Disease states:  Acute MI,Acute MI,  Heart failure with scar or hibernating myocardium,Heart failure with scar or hibernating myocardium,  Chronic ischemia not amenable to conventionalChronic ischemia not amenable to conventional revascularizationrevascularization
  9. 9. Skeletal myoblasts • Myoblasts derived from satellite cells in skeletal muscle • With appropriate stimulus, satellite cells differentiate into muscle fibres • Highly resistant to ischemia • Do not contract spontaneously • Do not differentiate into cardiomyocytes • Orient towards cardiac stress reducing thinning and dilation • Improve diastolic and systolic function Potential risk of fatal arrhythmia;
  10. 10. Human studies with cell therapy inHuman studies with cell therapy in cardiovascular diseasescardiovascular diseases  Cell types:Cell types:  Endothelial progenitor cellsEndothelial progenitor cells::  Bone marrow mononuclear cells,Bone marrow mononuclear cells,  Bone marrow endothelial progenitors eg. CD34+, CD133+ etcBone marrow endothelial progenitors eg. CD34+, CD133+ etc  Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion)  Cord bloodCord blood  Skeletal myoblastsSkeletal myoblasts  Mesenchymal stem cellsMesenchymal stem cells  Resident cardiac stem cellsResident cardiac stem cells  Adipose tissue progenitorsAdipose tissue progenitors  Disease states:Disease states:  Acute MI,Acute MI,  Heart failure with scar or hibernating myocardium,Heart failure with scar or hibernating myocardium,  Chronic ischemia not amenable to conventionalChronic ischemia not amenable to conventional revascularizationrevascularization
  11. 11. Allogeneic Mesenchymal Stem Cells forAllogeneic Mesenchymal Stem Cells for Acute Myocardial InfarctionAcute Myocardial Infarction  60 patients enrolled60 patients enrolled  Baseline EF~50%Baseline EF~50%  Intravenous adult humanIntravenous adult human MSCs (Provacel™, OsirisMSCs (Provacel™, Osiris Therapeutics) given 1-10 daysTherapeutics) given 1-10 days after infarct (vs. placebo)after infarct (vs. placebo)  No increase in adverse eventsNo increase in adverse events  No difference in baseline EFNo difference in baseline EF  LAD infarcts:LAD infarcts:  MSC therapy: increase in EFMSC therapy: increase in EF at 3 (48.8 ± 11.9 vs 57.1 ± 8.2;at 3 (48.8 ± 11.9 vs 57.1 ± 8.2; P 0.02) and and 6 monthsP 0.02) and and 6 months (56.3 ± 8.7; P=0.05).(56.3 ± 8.7; P=0.05).  Changes in EF in the placeboChanges in EF in the placebo patients and the non-LADpatients and the non-LAD groups were not significantgroups were not significant Hare JM, et al., ACC Scientific Sessions 2007 (abstract) Zambrano, T, et al., Circulation. 2007;116:II_202. (abstract)
  12. 12. Human studies with cell therapy inHuman studies with cell therapy in cardiovascular diseasescardiovascular diseases  Cell types:Cell types:  Endothelial progenitor cellsEndothelial progenitor cells::  Bone marrow mononuclear cells,Bone marrow mononuclear cells,  Bone marrow endothelial progenitors eg. CD34+, CD133+ etcBone marrow endothelial progenitors eg. CD34+, CD133+ etc  Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion)  Cord bloodCord blood  Skeletal myoblastsSkeletal myoblasts  Mesenchymal stem cellsMesenchymal stem cells  Resident cardiac stem cellsResident cardiac stem cells  Disease states:Disease states:  Acute MI,Acute MI,  Heart failure with scar or hibernating myocardium,Heart failure with scar or hibernating myocardium,  Chronic ischemia not amenable to conventionalChronic ischemia not amenable to conventional revascularizationrevascularization
  13. 13. Human studies with cell therapy inHuman studies with cell therapy in cardiovascular diseasescardiovascular diseases  Cell types:Cell types:  Endothelial progenitor cellsEndothelial progenitor cells::  Bone marrow mononuclear cells,Bone marrow mononuclear cells,  Bone marrow endothelial progenitors eg. CD34+, CD133+ etcBone marrow endothelial progenitors eg. CD34+, CD133+ etc  Peripheral blood progenitors (ex vivo expansion)Peripheral blood progenitors (ex vivo expansion)  Cord bloodCord blood  Skeletal myoblastsSkeletal myoblasts  Mesenchymal stem cellsMesenchymal stem cells  Resident cardiac stem cellsResident cardiac stem cells  Disease states:Disease states:  Acute MI,Acute MI,  Heart failure with scar or hibernating myocardium,Heart failure with scar or hibernating myocardium,  Chronic ischemia not amenable to conventionalChronic ischemia not amenable to conventional revascularizationrevascularization
  14. 14. Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure • Perrin E Circulation 2003 Biosense Webster Myostar/ NOGA catheter
  15. 15. Losordo D et al ACC 2009
  16. 16. Losordo D et al ACC 2009
  17. 17. Disease states: – Acute MI, – Heart failure with hibernating myocardium – Myocardial ischemia and unrevascularizable disease – Peripheral arterial disease Clinical trials with endothelial progenitor cells
  18. 18. 18 Potential mechanisms of benefit of bonePotential mechanisms of benefit of bone marrow derived cells after myocardialmarrow derived cells after myocardial infarctioninfarction Potential mechanisms of stem cells in cardiac repair. Transdifferentiation to cardiomyocytes Attenuation of Remodelling Arteriogenesis or Angiogenesis Mollmann, H. et al. Heart 2009;95:508-514 Figure 1 Potential mechanisms of stem cells in cardiac repai Paracrine effects Cell fusion Reduction of apoptosis Promoting endogenous Cardiac stem cell function
  19. 19. Improvement in left ventricular ejection fraction (LVEF) in patientsImprovement in left ventricular ejection fraction (LVEF) in patients treated with bone marrow-derived cells (BMCs)treated with bone marrow-derived cells (BMCs) • More than 1200 patients with STEMI randomized • Modest improvement in ejection fraction (EF 3%) • Reduction in infarct size • Reduction in end-systolic volume Comparison with pharmacological therapy post MI: Capricorn study (Carvedilol vs. placebo after AMI EF<40%): EF increased by 3.9% and end-systolic volume by 9.2 mls. Mortality reduced by 25%. Enca Martin-Rendon Eur Heart J 2008; 29:1807 Abdel-Latif, A. et al. Arch Intern Med 2007;167:989-997 .Lipinski et al J Am Coll Cardiol; 2007;50:1761
  20. 20. 20 Emory University, Atlanta, GA ; Vanderbilt University, Nashville, TN; Lindner Center, Cincinnatti, Ohio; Texas Heart Institute Primary Objective Feasibility and safety of intra-coronary infusion of autologous CD34+ cells at three dose levels (5, 10, 15 million). Secondary Objective To assess the effect on cardiac function (MRI, echo) and infarct region perfusion (SPECT) . Assess mobility/homing (CXCR-4), viability and in vitro hematopoietic and precursor cell growth (CFU-G). Only study to investigate cell dose-response Largest dose of i.c. CD34+ cells given to date Bone marrow CD34+ cell injection afterBone marrow CD34+ cell injection after STEMI (AMRS 1)STEMI (AMRS 1)
  21. 21. Chest pain + STEMI Stenting + Usual medical Rx Day 1-9 Bone marrow harvest Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRIIntracoronary cell product infusion Days 1-10 cell product Screening Echo EF <50% SPECT MRI Intracoronary bone marrow mononuclearIntracoronary bone marrow mononuclear cell injection after acute ST elevation MIcell injection after acute ST elevation MI Cell product concentration Figure 2 Application of stem cells into infarcted tissue by intracoronary transplantation. Cells are delivered over the lumen of an inflated over-the-wire balloon catheter placed in the reopened infarct artery. MI, infarcted myocardium.
  22. 22. ISOLEX is a trademark of Baxter International Inc. Progenitor cell Therapeutics, NJ Sterility Pyrogenicity Ex vivo viability
  23. 23. Paramagnetic CD34 Positive Cell Selection S S S S S S S S S SSS S Magnet SS S S S S Anti-CD34 mAb Paramagnetic bead SAM Ig antibody MNC Fraction Containing CD34+ Stem Cells Purified CD34+ Cells PR34+ Release Agent S S
  24. 24. Volume reduction of CD34+ selected cells
  25. 25. CD34+ cells are infused via the infarct related artery 6 to 9 days following successful coronary artery stenting. Intracoronary cell therapy trial : bone marrow CD34+ cell injection post acute ST elevation MI (AMR 1)
  26. 26. 26 Chest pain + STEMI Stenting + Usual medical Rx Day 1-9 Bone marrow harvest Assessments: Safety Functional Class Holter monitoring Treadmill Cardiac function: MRI, Echo Perfusion: SPECT, MRIIntracoronary cell product infusion Days 1-10 cell product Screening Echo EF <50% SPECT MRI Intracoronary bone marrow mononuclearIntracoronary bone marrow mononuclear cell injection after acute ST elevation MIcell injection after acute ST elevation MI Cell product concentration Figure 2 Application of stem cells into infarcted tissue by intracoronary transplantation. Cells are delivered over the lumen of an inflated over-the-wire balloon catheter placed in the reopened infarct artery. MI, infarcted myocardium.
  27. 27. Bone marrow CD34+ cell injection after STEMIBone marrow CD34+ cell injection after STEMI (AMRS 1)(AMRS 1) -5.7 mL vs. -0.1 mL +4% vs. +1% -10% vs. -3%
  28. 28. Resting perfusion: SPECT total severity score Resting total severity score Control, 5 million cells = +13 10, 15 million cells = -256 (p=0.01) Bone marrow CD34+ cell injection afterBone marrow CD34+ cell injection after STEMI (AMRS 1)STEMI (AMRS 1)
  29. 29. Intracoronary infusion of autologous bone marrow CD34+ cells during the repair phase after STEMI at higher doses than previously administered is safe, and may be associated with improved functional recovery from enhanced perfusion to the peri-infarct zone. Bone marrow CD34+ cell injection afterBone marrow CD34+ cell injection after STEMI (AMRS 1)STEMI (AMRS 1)
  30. 30. Bone marrow-derived cellBone marrow-derived cell therapy for AMItherapy for AMI • Ongoing studies: www.clinicaltrials.org – Worldwide: Ten studies – US: Bone marrow: Intracoronary administration • TIME (n=120), (NHLBI), • Late –TIME (n=87) (NHLBI), • Minneapolis (n=60) • CD34+ cells: AMRS (Amorcyte) -Allogeneic Mesenchymal Precursor Cells n=25 Direct myocardial injection (Angioblast Systems) - Mesenchymal Stem Cells (Provacel) Intravenous injection (Osiris)
  31. 31. Cell therapy trials in acute MI Quyyumi Lab: Jonathan Murrow M.D. Mick Ozkor MD. Saurabh Dhawan M.D. Riyaz Patel M.D. Ayaz Rehman MD A. Konstantinos M.D. Salman Sher Yusuf Ahmed Irina Uphoff Ibhar Al-Mheid Nino Kavtaratze Hamid Syed Shawn Arshad Progenitor Cell Laboratory W. Robert Taylor M.D., PhD Diane Sutcliffe Hematology/ Stem Cell Processing E. Waller M.D., PhD Sagar Lonial M.D. Kreton Mavromatis M.D. Ziyad Ghazzal M.D. Habib Samady M.D. Tanveer rab MD. Chandan Devireddy MD Henry Liberman MD Douglas Morris MD Emory Intereventional faculty AMRS1 Sponsor: Amorcyte Inc. PI: Arshed Quyyumi MD Clinical sites: Emory University, Atlanta, GA Vanderbilt University, TN Douglas Vaughan MD Lindner Center, Ohio Dean Keriakis MD Texas Heart Institute Jim Willerson MD Core labs: Fabio Esteves MD James Galt PhD Stam Lerakis MD John Oshinski PhD

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