Transcript Autologous Stem Cell Therapy: Using a Patient`s Own

Autologous Stem Cell Therapy:
Using a Patient’s Own Stem Cells
to Treat their Heart Disease
February 22, 2008
Douglas W. Losordo, M.D.
Northwestern University, Chicago, IL
1
Macro-Vessels as a Therapeutic Target
Circulation 1977
% Viable Myocardium
vs. Time of Occlusion
40m
3h
20
24h
3
hrs
6
hrs
2
24
hrs
Microvascular Obstruction is Associated with
Worse Outcome following Myocardial Infarction
3
Bogaert, Janssens et al, 2007
Event-free survival for patients with and
without MRI microvascular obstruction
No Microvascular Obstruction
Microvascular Obstruction
(clinical course without cardiovascular death, reinfarction,
congestive heart failure, or stroke)
Wu, K. C. et al. Circulation 1998;97:765-772
4
Copyright ©1998 American Heart Association
Micro-Vessels as a Therapeutic Target
Science 1992
From Asahara et al, AHA 2006
7
CD34+
= injected humanCD34+ Cell
= native Rat vessels
Neovascularization in Adult Mammals
EPCs
Growth factors
Cytokines
Hormones
Ischemia
Proliferation
Differentiation
Mobilization
Recruitment
Angiogenesis
Bone Marrow
Endothelial cells sprouting from
pre-existing blood vessels
Peripheral Blood
Target Organ
Vasculogenesis
in situ progenitor cell
proliferation
and differentiation
Hypothesis:
Autologous Human EPCs can
contribute to Therapeutic
Neovascularization of
Ischemic Tissue
Human EPC culture
Isolation of
peripheral blood
Mononuclear cell
Culture PBMNC
(PBMNC) separation from 500µl blood
Culture expansion
IV Injection in
Immunodeficient
Rat with
Myocardial
Ishcemia
DiI-acLDL Label
Atsuhiko Kawamoto, MD, P
I.V. transplantation of cultured EPCs
Transplanted Human EPCs Reduce The Extent of
Myocardial Fibrosis 28 Days after Myocardial Ischemia
in Rats
Elastic tissue-trichrome staining
EPC
Medium
Kawamoto A, et al. Circulation. 2001.
Limitations for Clinical Application of
Ex-Vivo Expanded EPC Transplantation
•Regulatory issues regarding Culture Expansion of EPC in the US
•Primary scarcity of EPCs in circulation for Systemic transplantation
BW
Rat
Human
200 g
60 kg
EPC #
to be injected
106
3 X 108
Blood volume
to be drawn
20 ml
6,000 ml
New Strategy
Autologous and Local transplantation of Freshly-Isolated CD3
Recovery in LV Ejection Fraction
Injection of G-CSF–mobilized human CD34+ cells
into rats with acute infarction improves capillary
density and myocardial function.
CD34+ Cells
CD34- Cells
Kocher, Itescu et al
Nature Medicine
CD34+ Cells for
Neovascularization
of Ischemic Tissue
Myocardial Infarction in Nude
Rat CD34+ cells
Unselected MNC
Healthy Volunteer
Patients
Satoshi Shintani,
MD, PhD
Atsuhiko Kawamoto, MD, PhD
Treatment Groups
1) PBS: 100 µl
2) Low 34: 5X103 cells/ rat kg
3) Mid 34: 5X105 cells/ rat kg
4) Mid MNC: 5X105 cells/ rat
kg
5) High MNC: tMNCs
containing
Mid EPC
n=8~10 in each group
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Human CD34 Transplant Improves
Left Ventricular Function Post-MI
Fractional Shortening (%)
Regional Wall Motion Sco
50
40
30
*
*
*
28
*
*
*
*
24
20
20
10
0
Low Mid Mid Hig 16
Low Mid Mid High
PBS
PBS
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34 34 MNC h
34 34 MNCMNC
Infarct Size: Patient vs. Healthy
Cells
%LV Fibrotic Area
**
* P<0.05
*
** P<0.01
*
PBS
105
105
105
PMNCs PCD34+ HCD34+
Nude Rat
Clothed Human
Not to scale
Study Design: Double Blind, Placebo Controlled,
Dose Escalating
Patient population
(n=24)
•>21 yrs
•CCS1 class III or IV
•Angina
•Attempted “best”
medical therapy2
•Non-candidate for
•surgical revasc.
•Ischemia on SPECT
•1-6 min. Bruce protocol
with angina or anginal
equivalent at baseline
5X104
Day 5 OutPt
Leukopheresis
Day 6 In Hospital
NOGA mapping &
injection of CD34+ cells
X 10 (0.2 mL each)
1X105
5X105
Follow-up
1,2,4 wks
2,3,6,9,12 mos
GCSF
5 μg/kg/d
for 5 days
Day 6
Selection (Isolex®)
& purification
placebo
Cell
dose
(CD34+
cells/kg)
Day 7
Discharge
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Human Intramyocardial
Autologous CD34+ Cell Transplantation
QuickTime™ and a
DivX 4.1.2 decompressor
are needed to see this picture.
Angina frequency
40
Angina
Frequency
Change
from
Baseline
Episodes
per Week
Placebo
CD34
20
0
-20
-40
3
6
Months
Circulation. 2007;115:3165-3172.
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Nitroglycerin consumption
Placebo
CD34
80
Change
from
Baseline in
NTG Tablets
consumed
per week
30
-20
-70
3
6
Months
Circulation. 2007;115:3165-3172.
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Patient A.S.: NOGA Mapping and
Intramyocardial Injection
Intramyocardial
Voltage Map
injection
- LAO sites
Local Linear Shortening - LAO
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Time (minutes)
Patient AS: Exercise treadmill times
after Autologous CD34+ Cell Injection
9
8
7
6
5
4
3
2
1
0
Treadmill
time
Time to
Angina
Baseline
3 months
6 months
No angina
during
ETT at 6
month FU
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Patient A.S.: SPECT findings – Progressive
Improvement in Perfusion At Rest and
Post-stress Over 6 month Follow-up
Baseline
3 months
6 months
Stress
Rest
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A New Era for
Treatment of Vascular Disease?
1. Medical Therapy
2. Mechanical Revascularization
3. Biological Repair
Acknowledgements
• NHLBI
•FDA
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Thank you for your attention!
"The Heart," from Traite de Medecine by Aldebrande de Florence, French School, 1356