Transcript Progenitor Cell Therapy, LLC

Stem Cells in cardiovascular diseases
Arshed A. Quyyumi MD; FRCP
Professor of Medicine
Division of Cardiology
Emory University School of
Medicine
Atlanta, Georgia, USA
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
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)
Adult Bone Marrow Stem Cell Plasticity
Neural cells
Epidermal cells
Ectodermal
Progenitor Cells
Endothelial Progenitor
Cells
Blood cells
Mesodermal
Progenitor Cells
Hematopoeitic
cells
Bone Marrow
Stem Cells
Endodermal
Progenitor Cells
Hepatocytes
Resident stem cells:
Heart, skeletal muscle,
Adipose tissue, brain,
Lung etc.
Stromal or
Mesenchymal
MAPC
Osteocytes,
Chondrocytes
Myocytes (Skeletal)
(Cardiac)
VEGF
Endothelial cells
PDGF
Smooth muscle cells
Hypoxia
HIF-1
SDF-1
CXCR4
Rafii S & Lyden D Nature Medicine 9, 702 - 712 (2003)
Cerdani DJ Nat Med 2004
Human studies with cell therapy in
cardiovascular diseases
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Cell types:
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Endothelial progenitor cells:
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Bone marrow mononuclear cells,
Bone marrow endothelial progenitors eg. CD34+, CD133+ etc
Peripheral blood progenitors (ex vivo expansion)
Cord blood
Skeletal myoblasts
Mesenchymal stem cells
Resident cardiac stem cells
Adipose tissue progenitors
Disease states:
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Acute MI,
Heart failure with scar or hibernating myocardium,
Chronic ischemia not amenable to conventional revascularization
Delivery options for stem cells
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Intracoronary
Coronary sinus
Direct myocardial
injection epicardial,
endocardial),
Intravenous
Bone marrow
mobilization
Delivery devices
Human studies with cell therapy in
cardiovascular diseases

Cell types:

Endothelial progenitor cells:








Bone marrow mononuclear cells,
Bone marrow endothelial progenitors eg. CD34+, CD133+ etc
Peripheral blood progenitors (ex vivo expansion)
Cord blood
Skeletal myoblasts
Mesenchymal stem cells
Resident cardiac stem cells
Disease states:

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Acute MI,
Heart failure with scar or hibernating myocardium,
Chronic ischemia not amenable to conventional revascularization
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;
Human studies with cell therapy in
cardiovascular diseases

Cell types:

Endothelial progenitor cells:









Bone marrow mononuclear cells,
Bone marrow endothelial progenitors eg. CD34+, CD133+ etc
Peripheral blood progenitors (ex vivo expansion)
Cord blood
Skeletal myoblasts
Mesenchymal stem cells
Resident cardiac stem cells
Adipose tissue progenitors
Disease states:

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Acute MI,
Heart failure with scar or hibernating myocardium,
Chronic ischemia not amenable to conventional revascularization
Allogeneic Mesenchymal Stem Cells for
Acute Myocardial Infarction
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60 patients enrolled
Baseline EF~50%
Intravenous adult human MSCs
(Provacel™, Osiris
Therapeutics) given 1-10 days
after infarct (vs. placebo)
No increase in adverse events
No difference in baseline EF
LAD infarcts:
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MSC therapy: increase in EF at
3 (48.8 ± 11.9 vs 57.1 ± 8.2;
P 0.02) and and 6 months
(56.3 ± 8.7; P=0.05).
Changes in EF in the placebo
patients and the non-LAD
groups were not significant
Hare JM, et al., ACC Scientific Sessions 2007 (abstract)
Zambrano, T, et al., Circulation. 2007;116:II_202. (abstract)
Human studies with cell therapy in
cardiovascular diseases

Cell types:

Endothelial progenitor cells:








Bone marrow mononuclear cells,
Bone marrow endothelial progenitors eg. CD34+, CD133+ etc
Peripheral blood progenitors (ex vivo expansion)
Cord blood
Skeletal myoblasts
Mesenchymal stem cells
Resident cardiac stem cells
Disease states:



Acute MI,
Heart failure with scar or hibernating myocardium,
Chronic ischemia not amenable to conventional revascularization
Human studies with cell therapy in
cardiovascular diseases

Cell types:

Endothelial progenitor cells:








Bone marrow mononuclear cells,
Bone marrow endothelial progenitors eg. CD34+, CD133+ etc
Peripheral blood progenitors (ex vivo expansion)
Cord blood
Skeletal myoblasts
Mesenchymal stem cells
Resident cardiac stem cells
Disease states:



Acute MI,
Heart failure with scar or hibernating myocardium,
Chronic ischemia not amenable to conventional revascularization
Transendocardial, Autologous Bone
Marrow Cell Transplantation for Severe,
Chronic Ischemic Heart Failure
•
Biosense Webster Myostar/ NOGA catheter
Perrin E Circulation 2003
Losordo D et al ACC 2009
Losordo D et al ACC 2009
Clinical trials with endothelial progenitor
cells
Disease states:
– Acute MI,
– Heart failure with hibernating myocardium
– Myocardial ischemia and unrevascularizable
disease
– Peripheral arterial disease
Figure 1 Potential mechanisms of stem cells in cardiac repai
Potential mechanisms of benefit of bone
marrow derived cells after myocardial
Potential mechanisms of stem cells in cardiac repair.
infarction
Transdifferentiation
to cardiomyocytes
Attenuation of
Remodelling
Arteriogenesis or
Angiogenesis
Paracrine effects
Cell fusion
Reduction of apoptosis
Promoting endogenous
Cardiac stem cell
function
Mollmann, H. et al. Heart 2009;95:508-514
Improvement in left ventricular ejection fraction (LVEF) in patients
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
Enca Martin-Rendon Eur Heart J 2008; 29:1807
mls. Mortality reduced by 25%.
Abdel-Latif, A. et al. Arch Intern Med 2007;167:989-997
.Lipinski et al J Am Coll Cardiol; 2007;50:1761
Bone marrow CD34+ cell injection after
STEMI (AMRS 1)
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
Intracoronary bone marrow mononuclear
cell injection after acute ST elevation MI
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.
Chest pain + STEMI
Stenting +
Usual medical Rx
Screening Echo
SPECT
MRI
EF <50%
Cell
product
Day 1-9
Bone marrow
harvest
cell
product
concentration
Intracoronary cell
product infusion
Days 1-10
Assessments:
Safety
Functional Class
Holter monitoring
Treadmill
Cardiac function:
MRI, Echo
Perfusion:
SPECT, MRI
Progenitor cell
Therapeutics, NJ
Sterility
Pyrogenicity
Ex vivo viability
ISOLEX is a trademark of Baxter International Inc.
Paramagnetic CD34 Positive Cell Selection
S
Paramagnetic bead
Anti-CD34 mAb
S
Magnet
S
S
MNC Fraction Containing
CD34+ Stem Cells
Purified CD34+
S
S
S
S
SAM Ig antibody
PR34+ Release Agent
S
S S
Cells
S
S
S
S
S
S
S
S
S
Volume reduction of CD34+ selected cells
Intracoronary cell therapy trial : bone marrow
CD34+ cell injection post acute ST elevation MI
(AMR 1)
CD34+ cells are infused
via the infarct related artery
6 to 9 days following
successful coronary
artery stenting.
Intracoronary bone marrow mononuclear
cell injection after acute ST elevation MI
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.
Chest pain + STEMI
Stenting +
Usual medical Rx
Screening Echo
SPECT
MRI
EF <50%
Cell
product
Day 1-9
Bone marrow
harvest
cell
product
concentration
Intracoronary cell
product infusion
Days 1-10
Assessments:
Safety
Functional Class
Holter monitoring
Treadmill
Cardiac function:
MRI, Echo
Perfusion:
SPECT, MRI
Bone marrow CD34+ cell injection after STEMI
(AMRS 1)
-5.7 mL vs. -0.1 mL
+4% vs. +1%
-10% vs. -3%
Bone marrow CD34+ cell injection after
STEMI (AMRS 1)
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 after
STEMI (AMRS 1)
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-derived cell
therapy 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)
Cell therapy trials in acute MI
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
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