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Why Allogeneic Cells?

Why Allogeneic Cells?. Marc S. Penn, MD, PhD, FACC Skirball Laboratory for Cardiovascular Cellular Therapeutics Director, Center for Cardiovascular Cell Therapy Director, Bakken Heart-Brain Institute Departments of Cardiovascular Medicine, Biomedical Engineering and Stem Cell Biology

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Why Allogeneic Cells?

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  1. Why Allogeneic Cells? Marc S. Penn, MD, PhD, FACC Skirball Laboratory for Cardiovascular Cellular Therapeutics Director, Center for Cardiovascular Cell Therapy Director, Bakken Heart-Brain Institute Departments of Cardiovascular Medicine, Biomedical Engineering and Stem Cell Biology Senior Medical Director, Emerging Businesses

  2. Company NameCurrent Relationship Juventas Therapeutics CSO, Equity, Inventor Intellect, Inc.Equity, Inventor Cour Pharmaceuticals CMO, Equity Prognostix, Inc.CMO, Equity, Inventor Cardionomic, Inc.Equity, Inventor BioHeart, Inc., SAB Member, Licensee Oakwood Medical VenturesVenture Partner Cardax Pharmaceuticals SAB Member Athersys, Inc. Sponsored Research SDG, Inc. Sponsored Research CCO Technologies Sponsored Research Cell Targeting Sponsored Research Southwest Michigan FundConsultant MPI ResearchConsultant Disclosures 03/2009

  3. In Vivo Studies Confirm Favorable Immunological Profile • Immunosuppression not required with MultiStem used allogeneically or xenogeneically (human → rodent) for benefit in acute MI or stroke models • MultiStem serial administration safe → no evidence of allo-antibody / T-cell sensitization response • MultiStem appears to modulate immune / inflammatory response regionally, not globally • No interference with systemic immune response, as evaluated in ovalbumin antigen challenge studies • MultiStem homes / accumulates in sites of injury in preclinical animal models 3

  4. Cell Types of Interest Totipotent Embryonic Stem Cells Umbilical Cord Stem Cells MAPCs Pluripotent Hematopoietic SC CD117+, CD34+ Mesenchymal SC CD117-, CD34-, SH-1+ Cardiac Myocytes, Neurons Monocytes, Neutrophils, . . . . Endothelial Cells, Hepatocytes Skeletal Myoblasts

  5. Direct Comparison of the Effects of Allogeneic and Syngeneic MAPC • LAD ligation in Lewis Rat • Genetically marked MAPC from • Lewis Rat (syngeneic) • SD Rat (allogeneic)

  6. Vascular Effects of MAPC vWF SMA Overlay PBS Lewis SD

  7. MAPC into Lewis Rat at Time of Acute MI 75% 51% Source of MAPC 6 weeks after Acute MI10 million MAPC or Saline at time of MI

  8. Allogeneic and Syngeneic MAPC Survival and Engraftment 1 Week 6 Weeks Lewis -> Lewis Lewis -> SD

  9. Syngeneic and AllogeneicMAPC Survival Weeks after AMI MAPC Engraftment (Cells / mm2) Lewis-> Lewis Lewis->SD Recipient Strain Cells Injected at the time of AMI

  10. MultiStem® Immuno-Privileged In Vitro Mixed Lymphocyte Reaction MultiStem does not elicit In Vitro T-Cell Response in MLR Studies Donor 1 Cells (Rare alloreactive T-cells in red) Donor 2 Cells Mixture Allogeneic T-cell controls Recognition of allogeneic cells causes T-cell activation and proliferation Proliferation measurable by increase DNA synthesis T-cells don’t react to MultiStem (MAPC) Self to self 10

  11. MultiStem® Immunosuppress Allogeneic T Cells MultiStem (like MSC) Exhibits Immunosuppressive Effects On MLR (human) Dose Dependent Suppression of Allogeneic T Cell Response in MLR (Lewis rat) MAPC (MultiStem) Suppresses Immune Response Dose Dependent Effect 11

  12. MultiStem Non-Interference with Systemic Immune Response • Healthy buffalo rats immunized IP with ovalbumin (OVA) • Antibody study • Multiple MultiStem injections and evaluation points over time • T-cell study • Single IV MultiStem injections • OVA-Antibodies: no difference between MultiStem-treated and PBS control groups • T-cell response: no difference between systemically-treated MultiStem and PBS groups Designs Results 12

  13. Summary • Certain stem cell types (MAPC and MSC) can be used for allogeneic delivery without immunosuppression • Advantages for this strategy include • Delivery of cells at the time of PCI • Cells from healthy and young donors • Appear to deliver paracrine factors as well as autologous • Disadvantages • Long-term survival not yet demonstrated

  14. Need for Long-term Cell Survival

  15. Optical Mapping Voltage sensitive dye: Di-4-ANEPPS

  16. Arrhythmia and Cell Therapy at the Time of AMI 2 Million SKMB Direct Injection 2 Million MSC IV Infusion Saline N=8-10 animal / group 1 month after AMI

  17. Effect on Electrical Stability 1 month after MI * 100 80 Percent Inducible 60 40 * 20 0 SKMB Saline MSC Ctrl No MI Direct Injection IV Infusion *p<0.05 vs. Saline Control

  18. MSC Connexin Expression in vivo Connexin Overlay MSC Cx40 Cx43 Cx45

  19. Acknowledgements Funding Sources American Heart AssociationNIH Shalom Foundation Skirball Foundation State of Ohio Wilson Foundation • Commecial Collaborations • Athersys • - MAPC studies • Bioheart Inc • SKMB:SDF-1 Preclinical and Clinical trials • Juventas Therapeutics • - SDF-1 Clinical Development

  20. Acknowledgements CCF Stephen Ellis, MD Ravi Nair, MD Phil Howe, PhD James Thomas, MD CWRU Stan Gerson, MD Maritza Mayorga, PhD Jing Bian, PhD Indu Deglurkar, MD Niladri Mal, MD Arman Askari, MD Samuel Unzek, MD Zoran Popovic, MD Soren Schenk, MD Nikolai Vasilyev, MD Kai Wang, MD, PhD Ming Zhang, MD, PhD Xiaorong Zhou, MD Mazen Khalil, MD Dominik Wiktor, MD Yu Peng, MD Udit Agarwal Srividia Sundararaman Amanda Finan Nikolai Sopko Farhad Forudi, BS Matthew Kiedrowski, BS Kristal Weber, BS

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