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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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slide1

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

disclosures
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

in vivo studies confirm favorable immunological profile
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

cell types of interest
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

direct comparison of the effects of allogeneic and syngeneic mapc
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)
vascular effects of mapc
Vascular Effects of MAPC

vWF

SMA

Overlay

PBS

Lewis

SD

mapc into lewis rat at time of acute mi
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

allogeneic and syngeneic mapc survival and engraftment
Allogeneic and Syngeneic MAPC Survival and Engraftment

1 Week

6 Weeks

Lewis -> Lewis

Lewis -> SD

syngeneic and allogeneic mapc survival
Syngeneic and AllogeneicMAPC Survival

Weeks after AMI

MAPC Engraftment

(Cells / mm2)

Lewis-> Lewis

Lewis->SD

Recipient Strain

Cells Injected at the time of AMI

multistem immuno privileged in vitro
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

multistem immunosuppress allogeneic t cells
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

multistem non interference with systemic immune response
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

summary
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
optical mapping
Optical Mapping

Voltage sensitive dye: Di-4-ANEPPS

arrhythmia and cell therapy at the time of ami
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

effect on electrical stability
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

slide18

MSC Connexin Expression in vivo

Connexin

Overlay

MSC

Cx40

Cx43

Cx45

acknowledgements
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
acknowledgements1
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