Cell Transplantation for the failing myocardium:
A UK perspective
Tony Gershlick
U.H. Leicester
BCIS meeting Bristol Sept 2005
Therapy for AMI –
•
Lysis v PPC
• Impact of time/treatment
Heart failure -strategies-
Medical treatment
Biventricular pacing
1 million UK heart failure
5% all admissions
1-2% health budget
Surgical cardiomyoplasty
Left ventricular assist device
Artificial hearts
Heart transplantation
Cell transplantation ?
Stem cells for myocardial dysfunction
Questions that (should) concern us in the UK
Question 1
Is the science sound ?
Endothelial progenitor cells
Intra myocardial primitive satellite cells
Primative BM stem cells
Skeletal muscle satellite cells
Volume 50(5): 589–610, 2002
The Journal of Histochemistry & Cytochemistry
Bone marrow transplantation –plenty of pre-clinical data
Transplanted adult bone marrow cells repair myocardial infarcts in mice.
Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P.
The left coronary artery was ligated and 5 hours later Lin- c-kit+ bone marrow cells obtained from
transgenic male mice expressing enhanced green fluorescent protein - injected into the healthy
myocardium adjacent to the site of the infarct.
9 days the damaged hearts were examined for regenerating myocardium.
A band of new myocardium was observed in 12 surviving mice.
The developing myocytes were small and resembled fetal and neonatal myocytes.
- positive for EGFP, Y chromosome, and several myocyte-specific proteins including cardiac myosin,
and the transcription factors GATA-4, MEF2, and Csx/Nkx2.5.
The cells were also
positive for connexin
43, acells
gap junction/intercalated disc component
Primative
BM stem
Primitive cardiomyogenic cells from bone marrow
Clin Invest, March 1999, Volume 103, Number 5, 697-70
Shinji Makino1,
ball-like or stick-like appearance
spontaneously beating
Fibroblast like
5-azacytidine
2/52
form myotube-like structures
beating cells were connected and
formed myotube-like structures
Peripheral blood mononuclear cells
Endothelial progenitor cells
1. Heamopoietic markers CD 34 + CD 133 +
2. Endothelial markers EGF -2
A
EPC transdifferentiate in-vitro into cardiomyocytes
Intracellular gap junctional coupling between rat
cardiomyocytes and human EPCs was demonstrated
Badorff et al, Circulation 2003;107:1024-1032
B
Human EPCs transplanted into rat infarct model day 7
Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor
Cells for Myocardial Ischemia Atsuhiko Kawamoto
Circulation. 2001;103:634
Angiogenic potential / neo-vascularisation
Myoblasts are satellite cells and exist in a quiescent state.
They have built in resistance to ischemia
Vol ume 50(5): 589–610, 2002
The Journal of Histochemistry & Cytochemistry
Myotubes with prominent normal Z
bands in myofilaments and peripheral
multiple nuclei in myotubes
grafted skeletal myotubes
replacing scar fibrosis
Myoblast grafts can survive and show a switch to slowtwitch fibres .
Do not become myocytes
Hagege et al, Lancet 2003;361:491-92
Science :Good
In-vitro, ex-vivo, animal data for
BMC,
EPC ,
Myoblast all have potential
Which will be clinically applicable ?
What is actually happening ?
Autologous bone marrow cells
Circulating progenitor cells
Ischaemia (AMI)
Skeletal myoblasts
Chronic Heart Failure
Manipulation of in-vivo cells
Questions that (should) concern us in the UK
Is the basic science sound
 Are the trials of sufficient quality to provide the
answers to the questions being asked ?
 Are the trials relevant to our current practice ?
MNC
MNC v
CPC
MNC
MNC
Circulation, December 10, 2002
•20 patients with reperfused acute myocardial infarction
received bone marrow-derived stem cells (n=9) CPC (n=11)250mls
•Non-randomized matched reference group
•Trial end-point: LVEF assessed by Echo and PET-Scan @
4 months follow-up and at one year
TOPCARE-AMI
LVEF
51.3%
8.2%
59.5%
Would they have got better 2 nd
to PCI anyway?
Improved myocardial viability
in the stem cells group
The Lancet, July 10, 2004
•First randomized clinical trial
•after successful percutaneous
coronary intervention (PCI):
30 patients control group,
30 patients bone-marrow cell group
•Primary endpoint: global left-ventricular ejection fraction
(LVEF) change from baseline to 6 months’ follow-up,
determined by cardiac MRI
BOOST
Mean in-stent restenosis in the infarct-related artery,
expressed as a percentage of luminal diameter, was
32% (SD 20) in the control group and 33% (23) in
the bone-marrow-cell group (p=0·88). Four patients
from the control group and seven from the bonemarrow-cell group presented with an in-stent
restenosis of at least 50% (p=0·28).
Problems with the acute ischaemic trials
Unanswered clinical trial questions
Trials don’t tell us which cells
Variable numbers of cells transplanted – both CPC and BMC
3-5% : (Stem cell selection~ 200 mls BM) Retention 3%
Benefit did not correlate with absolute numbers of CD 34 cells
Unselected and selected cell populations not compared
No dose ranging studies
Timing ? Early environment cyto-toxic 3- 7 days
Engraftment
? longer
Problems with the acute clinical trials
No clear messages re type cells, nos. and delivery
All P PCI
Small number subjects -pilot studies
(Mortality/ morbidity end point
“REPAIR AMI”
AHA
(1000 s patients)
No adequate controls (Bone marrow acquisition?, coronary manipulation ?)
Mode of Delivery
EF increases small
Who is likely to benefit ?
BOOST

Appropriate trials ?

Who most likely to benefit ?
 Cell type ?
o Which of these questions can be answered ?
o What is the UK involvement
o Can we add to the Clinical science?
UK Centres Involved in Stem Cell Therapy
UHL/ St Barts/ The London
Anthony Mather
Martin Rothman
John Martin
Eric Alton
Kings College Hospital
Jonathan Hill
AJ Shah
St Marys/ Brompton
Nic Peters
Philip Poole-wilson
UH Leicester
Jan Kovac
Manual Galinanes
Nilesh Samani
Tony Gershlick
Single Centre
Trial @ UHL
Failure of
thrombolysis
Successful R-PCI
Echo d 3 EF < 45%
Baseline MRI
SC or Heparinised
plasma d 4-5
P EP 4 mo MRI
Poor LV
Setting lysis +
RESCUE-PCI
Late phase
Clinical ‘stem cell’ trials - Barts and
the London NHS Trust/UCLH
• Randomised control trials using autologous bone
marrow derived mononuclear cells in patients
with:
– Heart failure 2o IHD - commenced 8/05 - 300 patients
– Dilated cardiomyopathy - recruiting - 200 patients
– AMI tx with primary angioplasty - funding sort - 200
patients
• PIs: A Mathur, M Rothman, J Martin
Which of these questions can be answered,
What is the UK involvement

Appropriate trials ?

Who most likely to benefit ?
 Cell type ?
Muscular Biopsy
•Myoblast cells liberated
through Enzymatic
Digestion intercellular
matrices
Alternative Therapies For the Treatment
of Ischemic Cardiomyopathy
40%
LVEF/NYHA IMPROVEMENT AT SIX MONTHS
35%
LVEF
% Change
30%
NYHA
37%
25%
20%
15%
10%
24%
25%
14%
5%
0%
Bi-V Pacing
MyoCell
Bi-V Pacing
MyoCell
Journal of the American College of Cardiology, Vol. 42, No. 12, 2003, Smits,
Serruys et al. Patient Study. Study sponsored by Bioheart, Inc.
3 month, P=0.009, n=5; 6 month, P= 0.23, n=5.
SAFETY: Multi center phase 1 trial
6 pts
No ICD at
Baseline
#102: VT at
1mfup; resolved
#201: NSVT
3.5mfup; ICD
implanted
15 pts
enrolled
3 pts
event free
9 pts with
ICD in
place
5 pts
event free
#105: arrhythmias at
2mfup: ICD pacing
#107: tachycardia
during 6min-walk:
firing ICD
#204: NSVT/VT 1 week
post proc. Slow VT, Elec
storm: firing ICD; patient
died
#4003:died 9
days post proc
#207: slow VTs 1
week post proc:
manual termination
Bioheart Percutaneously Delivered
Myoblasts EU Phase II Trial (SEISMIC™)
Screening:
46 ICD patients
Baseline Evaluation
Visit 1 (Week -6)
ICD EF > 20% < 40 %
8 European Centres 3 UK :
Glenfield, (AHG,JK) Leicester
St Marys (Nic Peters)
Royal Brompton (Philip Poole-Wilson
Randomization :
ICD patients: 30 MyoCell ™, 16 Standard medical therapy
Treatment Arm
(Myocell TM 150-800 x 10 6)
Control Arm
(Standard Medical Therapy)
30 ICD patients
-
16 ICD patients
Enrollment Began June 2005.
SEISMIC Safety Endpoints
Primary:
– Defined Serious Adverse Events (SAEs)
Secondary:
–
–
–
–
Routine Clinical laboratory test results
Holter monitoring, 12-lead ECG data
Overall patient survival
Assessment of the safety of the use of the
MyoCath™, by Adverse Event assessment
SEISMIC Efficacy
Endpoints
Primary:
– Change in LVEF at 3 and 6 months by MUGA
compared with baseline
Secondary:
– QOL Assessments (6-min. walk, NYHA class)
– Hospitalization, readmissions or the need for
medical treatment outside of hospitalizations
– Echocardiography (global contractility, wall
thickness and coronary perfusion
improvements)
?
UK Infra structure
British Collaborative on Stem Cell Research and
the Heart
Objective: To form a collaborative group of basic
scientists and clinicians involved in research in stem
cells and the heart, in order to perform joint research.
• Four meetings held in UCL, average attendance 50
people.
• Three groups formed:
stem cells and vectors
animal models
clinical trials
British Collaborative on Stem Cell Research and
the Heart
• A “writing group” has met to define what clinical and
basic research needs to be done. Joint grants will be
applied for. A document will be circulated shortly.
• The clinical group will peer review protocols with an
emphasis on safety and necessity of studies.
• The group has a close connection to the European
Society of Cardiology Task Force on Stem Cells and the
Heart
General Summary and Conclusions
 Too soon to draw any conclusions
 Studies small, all PPCI, ? Safety concerns (restenosis)
 Promising
Bone-marrow stem cell
Post AMI patient
Advantages
•Pluripotent stem cells can
develop into cardiomyocytes
•Easy to isolate and grow well
in culture
Limitations
•New program of cell differentiation
program is required
•Efficiency of differentiation into adult
cardiomyocytes may be limited
•Some studies difficult to replicate
•Neovascularization can also
occur at the site of the scar
•Small trials
•Can improve myocardial
function
•UK PPCI makes applicability difficult
•LV improves anyway
Trials to date uncontrolled small numbers un-blinded
Skeletal myoblasts
Chronic HF AMI patient
Advantages
•Cells proliferate in vitro
•Ischemia resistant
•Transplanted cells can
differentiate into slow-twitch
myocytes, enabling cellular
cardiomyoplasty
•Reduce dilatation and
improve cardiac function
•Can use adult cells
Limitations
•Likely do not develop new
cardiomyocytes in vivo
•Electrical coupling to
surrounding myocardial cells
is probable but not definite
•Long-term stability of
differentiated phenotype is
unknown
•Arrhythmic potential
Transplantation of progenitor Cells
AMI patients
•Intracoronary infusions are safe and feasible
•Increase in global LVEF
•Improvement in wall motion abnormalities
•Reduction in LVESV
•Complete normalization of CFR(< so in BMC)
•Increases in myocardial viability
May need cytokines like G–CSF and this may be a problem
Stem Cell Tx appears to “work”
Issues and questions 1
How long will the transplanted cells survive?
Can they be safely delivered PCI/endocardially
Are they able to integrate? Modified
?
Do they have the ability to differentiate?
Will the cell transplant influence LV function?
Can we augment/enhance grafting, proliferation and function
of stem cell implants?
Is it safe ?
Issues and questions 2
How many cells do we need to transplant?
Which is the best way for delivery?
Should the donor cell chosen depend on the cause of heart
failure/ ventricular dysfunction ?
Which is the optimal time for cell transplantation?
What trials are needed to provide definitive answers ?
 UK is involved, central organisation,
▓ Funding, Regulatory bodies (MHRA,COREC)
collaboration, need for multi discipline are all challenges
Cell transplantation is an exciting development
Many questions
“EPC > Bone marrow > myoblasts “
NEED SUFFICIENTLY POWERED
RANDOMISED CONTROLLED TRIALS
1.
True quantity of effect
2.
That it is the SCT that is having any effect
3.
Safe
Something (UK) interventional cardiologists need to be involved in
Watch this space - new era for interventional cardiology
The Future of Stem Cells and the Heart
Need for double blind randomised trials in
myocardial infarction and heart failure of
autologous bone marrow cells. These should
be agreed nationally to avoid duplication.
The procedure should not be given as a treatment
to individual patients before results of above
trials.
A second wave of trials will follow using other
sources of cells, particular engineered.
UK Stem Cell Foundation