Cell Transplantation for the failing myocardium: A UK perspective Tony Gershlick U.H. Leicester BCIS meeting Bristol Sept 2005 Cell Transplantation for.

Cell Transplantation for the failing myocardium: A UK perspective Tony Gershlick U.H. Leicester BCIS meeting Bristol Sept 2005 Cell Transplantation for the failing myocardium: A UK perspective Tony Gershlick U.H. Leicester BCIS meeting Bristol Sept 2005

Cardiomyocytes do not regenerate after birth - respond to mitotic signals by cell hypertrophy rather than by cell hyperplasia. Loss of cardiomyocytes leads to regional contractile dysfunction- dead cardiomyocytes in infarcted ventricular tissues are progressively replaced by fibroblasts to form scar tissues. Some evidence heart is NOT a post-mitotic end organ Cardiomyocytes do not regenerate after birth - respond to mitotic signals by cell hypertrophy rather than by cell hyperplasia. Loss of cardiomyocytes leads to regional contractile dysfunction- dead cardiomyocytes in infarcted ventricular tissues are progressively replaced by fibroblasts to form scar tissues. Some evidence heart is NOT a post-mitotic end organ Impact of failed therapy AMI time 1 million UK heart failure 5% all admissions 1-2% health budget Impact of failed therapy AMI time 1 million UK heart failure 5% all admissions 1-2% health budget

Therapy for AMI Lysis v PPC Impact of time/treatment 1 million UK heart failure 5% all admissions 1-2% health budget Therapy for AMI Lysis v PPC Impact of time/treatment 1 million UK heart failure 5% all admissions 1-2% health budget Heart failure -strategies- Biventricular pacing Surgical cardiomyoplasty Left ventricular assist device Artificial hearts Heart transplantation Cell transplantation ? Medical treatment

Stem cells for myocardial dysfunction Questions that (should) concern us in the UK Do we (the cardiological/scientific community) have a good idea about Stem cells for myocardial dysfunction Questions that (should) concern us in the UK Do we (the cardiological/scientific community) have a good idea about Do we have the infra structure to be involved ? Do we have the infra structure to be involved ? Are the trials of sufficient quality to provide the answers to the questions being asked ? What dose/concentration Does the background science justify trial initiation Are the trials relevant to our current practice ? Is it safe ? Which studies is the UK involved in? Which in our (my) opinion is the likely way forward ? W hich in our (my) opinion is the likely way forward ? Which delivery technique Which cells

Question 1 Is the science sound ? Question 1 Is the science sound ? Stem cells for myocardial dysfunction Questions that (should) concern us in the UK

Primative BM stem cells Skeletal muscle satellite cells Endothelial progenitor cells Intra myocardial primitive satellite cells

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. Y chromosome - 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, a gap junction/intercalated disc component 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. Y chromosome - 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, a gap junction/intercalated disc component Primative BM stem cells Bone marrow transplantation plenty of pre-clinical data

Primitive cardiomyogenic cells from bone marrow Clin Invest, March 1999, Volume 103, Number 5, 697-70 Shinji Makino 1, Fibroblast like 5-azacytidine ball-like or stick-like appearance spontaneously beating 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 Endothelial progenitor cells 1. Heamopoietic markers CD 34 + CD 133 + 2. Endothelial markers EGF -2

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 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 A A B B Angiogenic potential / neo-vascularisation

Myoblasts are satellite cells and exist in a quiescent state. They have built in resistance to ischemia Myoblasts are satellite cells and exist in a quiescent state. They have built in resistance to ischemia

Skeletal myoblasts after MI -sheep model- Control Baseline Follow-up Grafted Baseline Follow-up P- valueLVEF(%)4343335024850.006 WMS8.91.4132.27.70.95.41.4

ICD or life vest if EF > 30 ICD EF > 20% < 40 % 46 patients 3 UK centres Glenfield, Leicester St Marys (Nic Peters) Royal Brompton (Philip Poole-Wilson) ICD EF > 20% < 40 % 46 patients 3 UK centres Glenfield, Leicester St Marys (Nic Peters) Royal Brompton (Philip Poole-Wilson)

Enrollment Began June 2005. Randomization ICD patients: 30MyoCell,16 Treatment Arm (Myocell TM 150-800 x 10 6 ) 30 ICD patients - Control Arm (Standard Medical Therapy) 16ICD patients Baseline Evaluation Visit 1 (Week Screening: 46 ICD patients Bioheart Percutaneously Delivered Myoblasts EU Phase II Trial (SEISMIC) : Standard medical therapy -6) ICD EF > 20% < 40 % 8 European Centres 3 UK : Glenfield, (AHG,JK) Leicester St Marys (Nic Peters) Royal Brompton (Philip Poole-Wilson ICD EF > 20% < 40 % 8 European Centres 3 UK : Glenfield, (AHG,JK) Leicester St Marys (Nic Peters) Royal Brompton (Philip Poole-Wilson

Bioheart US Phase I Trial (MYOHEART) Primary Inclusion Criteria Prior MI involving anterior, lateral, posterior or inferior walls > 12 weeks old at time of implant Patients with prior placement of an ICD > 30 days prior to implant LVEF > 20% and < 40% by MUGA at screening NYHA Class II or III Ablitiy to walk at least 300 meters during 6-minute walk test Need for revascularization ruled out by coronary angiogram or noninvasive stress test within 6 months of screening Target region wall thickness of > 6 mm by echocardiography Age > 30 and < 80 years old Prior MI involving anterior, lateral, posterior or inferior walls > 12 weeks old at time of implant Patients with prior placement of an ICD > 30 days prior to implant LVEF > 20% and < 40% by MUGA at screening NYHA Class II or III Ablitiy to walk at least 300 meters during 6-minute walk test Need for revascularization ruled out by coronary angiogram or noninvasive stress test within 6 months of screening Target region wall thickness of > 6 mm by echocardiography Age > 30 and < 80 years old

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 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) 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)

Restenosis

UK Infra structure

Questions that (should) concern us in the UK Do we (the cardiological/scientific community) have a good idea about Questions that (should) concern us in the UK Do we (the cardiological/scientific community) have a good idea about Do we have the infra structure be involved Do we have the infra structure be involved Are the trials of sufficient quality to provide the answers to the questions being asked ? What dose/concentration Does the background science justify trial initiation Are the trials relevant to our current practice ? Is it safe ? Which studies is the UK involved in? Which in our (my) opinion is the likely way forward ? Which delivery technique Which cells

Questions that (should) concern us in the UK Is the basic science sound 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 ? Maybe

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 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 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 T oo soon to draw any conclusions Studies small, all PPCI, ? Safety concerns (restenosis) Promising S tudies small, all PPCI, ? Safety concerns (restenosis) P romising

Bone-marrow stem cell Advantages Pluripotent stem cells can develop into cardiomyocytes Easy to isolate and grow well in culture Neovascularization can also occur at the site of the scar Can improve myocardial function Limitations New program of cell differentiation program is requiredNew program of cell differentiation program is required Efficiency of differentiation into adult cardiomyocytes may be limitedEfficiency of differentiation into adult cardiomyocytes may be limited Some studies difficult to replicateSome studies difficult to replicate Small trialsSmall trials LV improves anywayLV improves anyway UK PPCI makes applicability difficultUK PPCI makes applicability difficultLimitations New program of cell differentiation program is requiredNew program of cell differentiation program is required Efficiency of differentiation into adult cardiomyocytes may be limitedEfficiency of differentiation into adult cardiomyocytes may be limited Some studies difficult to replicateSome studies difficult to replicate Small trialsSmall trials LV improves anywayLV improves anyway UK PPCI makes applicability difficultUK PPCI makes applicability difficult Trials to date uncontrolled small numbers un-blinded Post AMI patient

Skeletal myoblasts 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 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 Chronic HF AMI patient

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 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 GCSF and this may be a problem

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 ? 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 ? Stem Cell Tx appears to work Issues and questions 1 Stem Cell Tx appears to work Issues and questions 1

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 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 NEED SUFFICIENTLY POWERED RANDOMISED CONTROLLED TRIALS Something (UK) interventional cardiologists need to be involved in Watch this space - new era for interventional cardiology Cell transplantation is an exciting development Many questions NEED SUFFICIENTLY POWERED RANDOMISED CONTROLLED TRIALS Something (UK) interventional cardiologists need to be involved in Watch this space - new era for interventional cardiology EPC > Bone marrow > myoblasts 1.True quantity of effect 2. That it is the SCT that is having any effect 3.Safe 1.True quantity of effect 2. That it is the SCT that is having any effect 3.Safe

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

Cell Transplantation for the failing myocardium: A UK perspective Tony Gershlick U.H. Leicester BCIS meeting Bristol Sept 2005 Cell Transplantation for.

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