Stem Cell and Gene Therapy for Cardiovascular Disease

482 Pages·2016·53.618 MB·English

by  Miller, Leslie William, Perin, Emerson C., Taylor, Doris A., Willerson, James T

STEM CELL AND GENE THERAPY FOR
CARDIOVASCULAR DISEASE
STEM CELL AND
GENE THERAPY FOR
CARDIOVASCULAR
DISEASE
Edited by
E C. P , M.D., P .D., FACC
MERSON ERIN H
Director,ResearchinCardiovascularMedicine;MedicalDirector,StemCellCenter,
TexasHeartInstitute,Houston,TX,USA
L W. M , M.D.
ESLIE ILLER
VisitingResearchandClinicalConsultant,TexasHeartInstitute,Houston,TX,USA
D A. T , P .D., FAHA, FACC
ORIS AYLOR H
Director,RegenerativeMedicineResearch;Director,CenterforCelland
OrganBiotechnology,TexasHeartInstitute,Houston,TX,USA
J T. W , M.D., FAHA, FACC
AMES ILLERSON
President,DirectorofCardiologyResearch,andCo-DirectoroftheCullenCardiovascular
ResearchLaboratories,TexasHeartInstitute,Houston,TX,USA
AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON
NEWYORK(cid:129)OXFORD(cid:129)PARIS(cid:129)SANDIEGO
SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO
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List of Contributors
Deborah D. Ascheim International Center for Health John P. Cooke Houston Methodist Research Institute,
Outcomes&InnovationResearch(InCHOIR),Department Houston,TX,USA
of Population Health Science & Policy, Icahn School of
H.J. Duckers Department of Experimental Cardiology,
Medicine at Mount Sinai; New York, NY, USA; Zena and
University Medical Center Utrecht, Utrecht, the
Michael A. Wiener Cardiovascular Institute, Icahn School
Netherlands
ofMedicineatMountSinai,NewYork,NY,USA
Victor J. Dzau Mandel Center for Hypertension Research
Wayne Balkan Interdisciplinary Stem Cell Institute,
andDukeCardiovascularResearchCenter,Departmentof
University of Miami Miller School of Medicine, Miami,
Medicine,DukeUniversityMedicalCenter,Durham,USA
FL,USA
Ray F. Ebert National Institutes of Health/National Heart,
Akshay Bareja Mandel Center for Hypertension Research
Lung,andBloodInstitute,Bethesda,MD,USA
and Duke Cardiovascular Research Center, Department
of Medicine, Duke University Medical Center, Durham, Jun Fujita Department of Cardiology, Keio University
USA SchoolofMedicine,Tokyo,Japan
Courtney E. Bartlett Division of Cardio-Thoracic Surgery, KeiichiFukuda DepartmentofCardiology,KeioUniversity
Department of Surgery, University of Utah, Salt Lake SchoolofMedicine,Tokyo,Japan
City,UT,USA Roberto Gaetani Department of Bioengineering, University
Atta Behfar Center for Regenerative Medicine, Mayo of California, San Diego, La Jolla, CA, USA; Sanford
Clinic,Rochester,MN,USA ConsortiumforRegenerativeMedicine,LaJolla,CA,USA
Lisle Blackbourn Division of Cardiovascular Medicine, Amir Gahremanpour Stem Cell Center and Adult
Department of Medicine, University of Wisconsin School Cardiology,TexasHeartInstitute,Houston,TX,USA
ofMedicineandPublicHealth,Madison,WI,USA W. Gathier Department of Experimental Cardiology,
Roberto Bolli Institute of Molecular Cardiology, Division University Medical Center Utrecht, Utrecht, the
of Cardiovascular Medicine, Department of Medicine, Netherlands
UniversityofLouisville,Louisville,KY,USA Annetine C. Gelijns International Center for Health
L. Maximilian Buja Cardiovascular Pathology Research Outcomes&InnovationResearch(InCHOIR),Department
Department, Texas Heart Institute, Houston, TX, USA; of Population Health Science & Policy, Icahn School of
Department of Pathology and Laboratory Medicine, the MedicineatMountSinai;NewYork,NY,USA
UniversityofTexasHealthScienceCenteratHouston,TX, Andrea S. Gobin Texas Heart Institute, Department of
USA RegenerativeMedicineResearch,Houston,TX,USA
Angela Castellanos Interdisciplinary Stem Cell Institute, Jose´ A. Gomez Mandel Center for Hypertension Research
University of Miami Miller School of Medicine, Miami, and Duke Cardiovascular Research Center, Department
FL,USA of Medicine, Duke University Medical Center, Durham,
Antoine H. Chaanine Cardiovascular Research Center, USA
MountSinaiSchoolofMedicine,NewYork,NY,USA
Roger J. Hajjar Cardiovascular Research Center, Mount
Eric Chau Texas Heart Institute, Department of SinaiSchoolofMedicine,NewYork,NY,USA
RegenerativeMedicineResearch,Houston,TX,USA
Joshua M. Hare Interdisciplinary Stem Cell Institute,
Zhen Chen Department of Medicine, UC San Diego, San University of Miami Miller School of Medicine, Miami,
Diego,CA,USA FL,USA
Karen L. Christman Department of Bioengineering, Nirmala Hariharan Department of Pharmacology,
University of California, San Diego, La Jolla, CA, USA; UniversityofCaliforniaDavis,Davis,CA,USA
Sanford Consortium for Regenerative Medicine, La Jolla,
Timothy D. Henry Cedars-Sinai Heart Institute, Los
CA,USA
Angeles,CA,USA
AmyChung NeoStem,Inc.,NewYork,NY,USA
William Hiesinger Division of Cardiovascular Surgery,
Robert M. Cole Cedars-Sinai Heart Institute, Los Angeles, Department of Surgery, University of Pennsylvania,
CA,USA Philadelphia,PA,USA
xi
xii
LISTOFCONTRIBUTORS
Alan T. Hirsch University of Minnesota Medical School, Brittany M. Penn The Ohio State University, Columbus,
Minneapolis,MN,USA OH,USA
Conrad P. Hodgkinson Mandel Center for Hypertension Marc S. Penn Summa Cardiovascular Institute, Summa
Research and Duke Cardiovascular Research Center, HealthSystem,Akron,OH,USA
Department of Medicine, Duke University Medical Emerson C. Perin Research in Cardiovascular Medicine,
Center,Durham,USA Stem Cell Center, Texas Heart Institute, Houston, TX,
Kimberly N. Hong Zena and Michael A. Wiener USA
Cardiovascular Institute, Icahn School of Medicine at Amish N. Raval Division of Cardiovascular Medicine,
MountSinai,NewYork,NY,USA Department of Medicine, University of Wisconsin School
KyungU.Hong InstituteofMolecularCardiology,Division of Medicine and Public Health, Madison, WI, USA;
of Cardiovascular Medicine, Department of Medicine, Department of Biomedical Engineering, University of
UniversityofLouisville,Louisville,KY,USA Wisconsin,Madison,WI,USA
Thomas E. Ichim Institute for Molecular Medicine, Micheline Resende Texas Heart Institute, Department of
HuntingtonBeach,CA,USA RegenerativeMedicineResearch,Houston,TX,USA
E. Marc Jolicoeur Montreal Heart Institute, Universite´ de Philip R. Roelandt Stem Cell Institute Leuven (SCIL),
Montre´al,Montre´al,Que´bec,Canada Leuven,Belgium
Kazuki Kodo Stanford Cardiovascular Institute, Stanford Valerie D. Roobrouck Stem Cell Institute Leuven (SCIL),
University, Stanford, CA, USA; Department of Medicine, Leuven,Belgium
DivisionofCardiology,StanfordUniversity,Stanford,CA, Luiz C. Sampaio Texas Heart Institute, Department of
USA RegenerativeMedicineResearch,Houston,TX,USA
Sandeep K. Krishnan Cedars-Sinai Heart Institute, Los Sean I. Savitz The University of Texas Health Science
Angeles,CA,USA CenteratHouston,Texas,USA
Michael J.B. Kutryk Interventional Cardiology Research, Eric G. Schmuck Division of Cardiovascular Medicine,
St. Michael’s Hospital; Department of Medicine, Faculty
Department of Medicine, University of Wisconsin
of Medicine, University of Toronto, Toronto, Ontario,
School of Medicine and Public Health, Madison, WI,
Canada USA
David S. Lee Department of Medicine, University of Ivonne Hernandez Schulman Interdisciplinary Stem Cell
CaliforniaSanFrancisco,SanFrancisco,CA
Institute, University of Miami Miller School of Medicine,
Randall J. Lee Department of Medicine, University of Miami,FL,USA
California San Francisco, San Francisco, CA; Robert D. Simari University of Kansas School of Medicine,
Cardiovascular Research Center, University of California KansasCity,KS,USA
San Francisco, San Francisco, CA; Institute for
Luis Felipe Silva Smidt Hospital Sa˜o Lucas and Hospital
Regeneration Medicine, University of California San
Moinhos de Vento, Porto Alegre, Brazil; Universidade
Francisco, San Francisco, CA; Division of Cardiology,
Federal do Rio Grande do Sul, Porto Alegre, Brazil; Texas
Section of Cardiac Electrophysiology, University of
HeartInstitute,Houston,TX,USA
California,SanFrancisco,CA
Rachel Ruckdeschel Smith Research and Development,
DouglasW.Losordo NeoStem,Inc.,NewYork,NY,USA
Capricor,Inc.,LosAngeles,CA,USA
EltonMigliati TexasHeartInstitute,Houston,TX,USA
Duncan J. Stewart Ottawa Hospital Research Institute;
LeslieW.Miller VisitingResearch andClinical Consultant, Department of Medicine, Faculty of Medicine, University
TexasHeartInstitute,Houston,TX,USA ofOttawa,Ottawa,Ontario,Canada
VivekMisra TheUniversityofTexasHealthScienceCenter Mark A. Sussman Department of Biology, San Diego State
atSanAntonio,Texas,USA University,SanDiego,CA,USA
Lem Moye´ University of Texas School of Public Health, Deephak Swaminath Summa Cardiovascular Institute,
Houston,TX,USA SummaHealthSystem,Akron,OH,USA
Nathalie Nguyen Department of Biology, San Diego State Sabrina Taldone Interdisciplinary Stem Cell Institute,
University,SanDiego,CA,USA University of Miami Miller School of Medicine, Miami,
Sang-GingOng StanfordCardiovascularInstitute,Stanford FL,USA
University, Stanford, CA, USA; Department of Medicine, Doris A. Taylor Texas Heart Institute, Department of
DivisionofCardiology,StanfordUniversity,Stanford,CA, RegenerativeMedicineResearch,Houston,TX,USA
USA
Andre Terzic Center for Regenerative Medicine, Mayo
Aaron Orozco Texas Heart Institute, Department of Clinic,Rochester,MN,USA
RegenerativeMedicineResearch,Houston,TX,USA
Jay H. Traverse Minneapolis Heart Institute at Abbott
Amit N. Patel Division of Cardio-Thoracic Surgery, NorthwesternHospital,UniversityofMinnesotaSchoolof
Department of Surgery, University of Utah, Salt Lake Medicine (cid:1) Cardiovascular Division, Minneapolis, MN,
City,UT,USA USA
xiii
LISTOFCONTRIBUTORS
Z. Tu¨rktas¸ Department of Experimental Cardiology, Y. Joseph Woo Department of Cardiothoracic Surgery,
University Medical Center Utrecht, Utrecht, the Stanford University School of Medicine, Palo Alto, CA,
Netherlands USA
Jessica Ungerleider Department of Bioengineering, James T. Willerson Director of Cardiology Research, and
University of California, San Diego, La Jolla, CA, USA; Co-Director of the Cullen Cardiovascular Research
Sanford Consortium for Regenerative Medicine, La Jolla, Laboratories,TexasHeartInstitute,Houston,TX,USA
CA,USA Joseph C. Wu Stanford Cardiovascular Institute, Stanford
Deborah Vela Cardiovascular Pathology Research University, Stanford, CA, USA; Department of Medicine,
Department,TexasHeartInstitute,Houston,TX,USA DivisionofCardiology,StanfordUniversity,Stanford,CA,
Catherine M. Verfaillie Stem Cell Institute Leuven (SCIL), USA; Institute of Stem Cell Biology and Regenerative
Leuven, Belgium; ReGenesys Corporation, Heverlee, Medicine, Stanford University School of Medicine,
Stanford,CA,USA
Belgium
BojanVrtovec AdvancedHeartFailureandTransplantation Alex Yaroshinsky AY Statistical Consulting, San Andreas,
CA,USA
Center, UMC Ljubljana, Department of Cardiology,
Ljubljana University Medical Center, Ljubljana, Slovenia; Lior Zangi Cardiovascular Research Center, Mount Sinai
Stanford Cardiovascular Institute, Stanford University SchoolofMedicine,NewYork,NY,USA
SchoolofMedicine,Stanford,CA,USA Jianyi (Jay) Zhang Department of Medicine, University of
Thomas Weber Cardiovascular Research Center, Mount MinnesotaMedicalSchool,Minneapolis,MN,USA
SinaiSchoolofMedicine,NewYork,NY,USA
Preface
The use of stem cells and genes has become an area limitations of their condition and the risk to their lives
of increasing research in both basic science and clinical and well being.
trials. This book provides a blend of these two areas The book is dedicated to all of the patients now
and is intended to provide the reader with the most afflicted and all those who are at risk, or will develop
up-to-date status of not only stem cell and genes, but cardiovascular disease in the future, and the growing
also progress in the area of tissue engineering to number of students, trainees, research scientists, and
enhance retention. These new therapeutic options are clinicians involved in the care of these patients with
intended for patients with all forms and stages of car- the goal of finding new therapeutic options to reduce
diovascular disease, with the goal of reducing the the limitations oftheircondition.
xv
Regenerative Medicine and the Cardiovascular
(cid:1)
System: A Good Start
James T. Willerson1, Leslie W. Miller2, Doris A. Taylor3, and
Emerson C. Perin4
1Director of Cardiology Research, and Co-Director ofthe Cullen Cardiovascular Research Laboratories, Texas Heart
Institute, Houston,TX, USA;2Visiting Research and Clinical Consultant, Texas Heart Institute, Houston,TX, USA;
3Texas HeartInstitute, Department ofRegenerative MedicineResearch, Houston, TX, USA; 4Research in
CardiovascularMedicine, Stem Cell Center,Texas Heart Institute, Houston, TX, USA
All humans are developmental products of stem contractility. Likewise, transendocardial injections of
cells. The union of our father’s sperm and our autologous bone marrow-derived aldehyde
mother’s egg generated billions of stem cells that dehydrogenase-bright stem cells in patients with ische-
through genetic signaling became every organ in our mic heart failure were found to be safe and to poten-
body and all about us, including our appearance, our tially contribute to improvements in perfusion and left
soul, and our intellect. Each of us also has a “rescue” ventricular (LV) function [9]. In a study examining the
system of stem cells circulating in the blood and resid- use of autologous adipose tissue-derived mesenchymal
ing in our heart (and other organs) that is intended to cells in patients with ischemic cardiomyopathy, the
repair injuries. However, early after birth, the heart’s cellswerefoundtobesafewheninjectedtransendocar-
ability to regenerate itself is inhibited [1]. Improving dially, and the treated patients showed preserved LV
our understanding of stem cells and building on the function and possible benefits in coronary blood flow,
capabilities of the rescue stem cell system may ulti- scar size,andLV contractility[7].Furthermore,astudy
mately enable researchers to use cell therapy not only by Bolli and colleagues [Cardiac Stem Cell Infusion in
to repair injuries locally, but also to regenerate the PatientswithIschemicCardiOmyopathy(SCIPIO)trial]
whole heart and other organs, when necessary. [2] showed that intracoronary infusion ofautologousc-
1
Although preclinical studies provide valuable informa- kit cardiacstemcellsaftercoronaryarterybypasssur-
tion, proof of the safety and efficacy of stem cell ther- gery was safe in patients with post-infarction LV dys-
apy has and will continue to come from studies in function, and that this treatment led to a significant
humans with cardiovascular diseases—the best model increase in LV ejection fraction (LVEF), a reduction in
for this work. Thus, we should carry on our human infarct scar size, and improvements in the New York
research of stem cell therapies as Shakespeare urged, Heart Association (NYHA) functional class and quality
“till truth makes all things plain.”† of life. In the CADUCEUS (CArdiosphere-Derived
Multiple small-scale clinical studies of cell therapy aUtologous stem CElls to reverse ventricUlar
forcardiovasculardiseaseshaveshownthatthesetreat- dySfunction)trial[4,5],investigatorsshowedthatintra-
mentsaresafeandmayprovideclinicalbenefits[2(cid:3)10]. coronary infusion of cardiosphere-derived cells (a mix-
Studieshaveexaminedavarietyofcelltypes,including ture of resident cardiac stem cells, including
1 1
bone marrow-derived mononuclear cells, bone mesenchymal cells, CD105 cells, and c-kit cells [11])
marrow-derived aldehyde dehydrogenase-bright stem obtained from endomyocardial biopsy specimens in
cells, adipose tissue-derived mesenchymal cells, and patients with recent large myocardial infarcts resulted
cardiac stem cells. For example, Perin and colleagues in reduced infarct mass and improved regional LV
[6] found transendocardial injections of autologous functioninpatientswithLVEFsof25%to45%.
bone marrow-derived mononuclear cells to be safe in Larger clinical studies have also shown the safety
patients with end-stage ischemic heart disease, and and potential efficacy of stem cell therapy in heart dis-
their findings suggested that the treatment may have ease [12(cid:3)15]. In the REPAIR-AMI (Reinfusion of
had positive effects on myocardial perfusion and Enriched Progenitor cells And Infarct Remodeling in
(cid:1)ModifiedfromamanuscriptpublishedinCirculationResearch2014;115(12);271(cid:3)78.
†AMidsummerNight’sDream,ActV,sc.1,line128.
xvii
xviii
REGENERATIVEMEDICINEANDTHECARDIOVASCULARSYSTEM:AGOODSTART
Acute Myocardial Infarction) study [13], for example, Beneficial results treating patients with coronary
1
the intracoronary administration of unfractionated heart disease and refractory angina with CD 34 cells
mononuclear cells taken from patients’ bone marrows by NOGA catheter have been reported in 167 patients
resulted in a small, but significant, increase in LVEF in who received 13105 or 53105 cells /hg of mobilized
1
patients with acute ST-segment elevation myocardial CD 34 cells or an equal volume of diluent [14].
infarction (MI) when the patients’ pretreatment LVEFs Patients with refractory angina who received intra-
were less than 48%. In treated patients from the same myocardial injections of autologous CD 341 cells (105
REPAIR-AMI trial, the risk of death, recurrent MI, and cells/hg) had significant improvements in angina fre-
rehospitalization also decreased [12]. In a trial from the quency and exercise tolerance [14]. Mathiasen et al.
Cardiovascular Cell Therapy Research Network, trans- showed similar benefit in treating patients with coro-
endocardial injections of autologous bone marrow- nary artery disease (CAD) and refractory angina with
derived mononuclear cells in patients with ischemic bone marrow-derived mesenchymal cells over a 3-year
cardiomyopathies and no other option for revasculari- follow-upwithreducedhospitaladmissionsforcardio-
zation resulted in a small but significant increase in vascular disease and excellent long-term safety [20].
LVEF [15].Thisincreasecorrelated with thepercentage Others have reported similar beneficial results in simi-
1 1
of CD34 and CD133 cells in the bone marrow sam- lar patients when bone marrow-derived stem cells
1
ples. Specifically, every 3% increase in CD34 or were used [21,22].
1
CD133 cells was associated with an absolute unit Clinical studies of stem cell therapy in patients with
increaseinLVEFof3%or5.9%,respectively,inamulti- ischemic cardiomyopathies have revealed several criti-
variable model that included age and treatment as pre- cal limitations and have raised important points to
dictor variables (P 5 0.04 for both). The therapeutic consider.Onemajorlimitationisthathumanstemcells
1
potential of CD34 cells has also been suggested by become dysfunctional with age [8,15,23]. In addition,
positive findings by Losordo et al. in a trial of patients stemcells becomelessableorunabletoreplicatethem-
with refractory angina where patients who received selves in older individuals (i.e., in those . 60 years of
intramyocardial injections of the low-dose treatment age) [8,23]. Furthermore, the absolute numbers of stem
(13105 autologous CD341 cells/kg body weight) cells in the bone marrow and in the circulation are
showedasubsequentdecreaseinanginafrequencyand reduced in older adults. Similarly, the number and
improvement in exercise tolerance [14]. Although these effectiveness of bone marrow-derived and circulating
examplessuggest that stemcelltherapymaybebenefi- stem cells are also reduced in patients with severe dis-
cial for some patients, the measurable effects have gen- eases and risk factors for cardiovascular disease
erally, even in larger trials, been modest. Thus, a better [24(cid:3)28]. Therefore, notwithstanding its elegance, the
understandingofthefactorsthatcontributetotheeffec- human rescue system of stem cells is unable to repair
tivenessofstemcelltherapyisneeded. damage in the hearts of those in whom repair is most
Adultstemcellshavealsobeenusedtotreatpatients often needed. Another potentially important limitation
with nonischemic cardiomyopathies. Vntovec et al. is that in many of the trials of stem cell therapy in
1
administered CD 34 cells to 28 patients by the intra- patients with cardiovascular disease, the composition
coronary route and had 27 control patients [16]. In the (i.e., the cellular make-up) and potency of the trans-
1
cell-treated patients, CD 34 cells were mobilized by planted cell product is different for each patient
granulocyte-colony stimulating factor and collected by because of the inherent heterogeneity of products iso-
aphaeresis. After a one-year follow-up, patients treated lated from individual patients. This likely contributes
with cells had an increase in LVEF from 25.5% to 30% to variations in outcomes. While these realizations are
(P 5 0.03) and a decrease in NT-pro BMP from sobering, they are also critical issues to consider when
2069 1 1996pg/ml to 1037 I 950pg/ml (P 5 0.01). A designing, implementing, and interpreting the results
secondary end point of one-year mortality or heart of any stem cell clinical trial involving patients with
transplantation was lower in patients receiving stem cardiovascular disease.
cell therapy (2/28, 7%) than in controls (8/27, 30%) As we learn the capabilities and limitations of spe-
(P 5 0.03), andthestemcelltherapywastheonly pre- cific stem cell populations through preclinical and clin-
dictor of outcome by multivariate analysis (P 5 0.04). ical research, we can use this information to design
The beneficial effect was sustained during a 5-year fol- more effective stem cell therapies. As noted above,
low-up [17] and was greater when the cells were given because the patients in these clinical studies are gener-
by the transendocardial rather than the intracoronary ally older and may have multiple co-morbidities, the
route of administration [18]. Similar benefit has been stem cells isolated from them may be less potent. One
reportedbyWangetal.whenautologousmesenchymal approach that can be used to circumvent this issue is
cells were used to treat patients with idiopathic dilated the use of allogeneic stem cells. Mesenchymal stem
cardiomyopathies[19]. cells, which can be found in the bone marrow, adipose
xix
REGENERATIVEMEDICINEANDTHECARDIOVASCULARSYSTEM:AGOODSTART
tissue, or myocardium, may not be immunologically allogeneicmesenchymalstem cells from youngdonors,
rejected when taken from one person and transplanted rejuvenated autologous stem cells, and/or specific
into another; thus, it appears to be feasible to use mes- combinations of stem cells that have been shown to
enchymal stem cells from youthful donors to treat produce better effects in relevant preclinical evalua-
aging individuals with cardiovascular diseases [29,30]. tions. In addition, because some patient-specific fac-
Indeed, when allogeneic mesenchymal cells from a tors, such as baseline bone marrow composition and
healthy young donor were injected transendocardially LVEF [13,15], have been shown to be associated with
into patients with ischemic or nonischemic cardiomy- improved outcomes after stem cell therapy, it may be
opathy, positive results were observed in those beneficial to select more targeted study populations in
patients who received a high cell dose, including future studies.
improved LV function and coronary blood flow and Every human being has an elegant system of rescue
substantially reduced rates of death, progressive heart stem cells that potentially may enhance the repair pro-
failure,and hospital readmission [29]. cess after injury. We must find ways to maximize the
Another approach that could be used to improve benefits of this system and the body’s stem cells by
cell therapy in patients who are older and may have producing cell therapies that can repair and regenerate
multiple co-morbidities is to rejuvenate the patient’s organs and possibly even delay the aging process. As
senescent stem cells. In a study by Madonna and col- with most medical breakthroughs, the development of
leagues [1], the induced overexpression of telomerase successful stem cell therapies will be achieved through
reverse transcriptase and myocardin in mesenchymal small, incremental improvements. Clinical trials are a
stromal cells from aged mice resulted in improvements vital part of this process because proof of the safety
in cell function both in vitro and in vivo. Likewise, and efficacy of stem cell therapy can come only from
ex vivo modification of senescent human cardiac pro- studies in humans with cardiovascular disease.
genitor cells with PIM-1 kinase has been shown to Ultimately, we have the opportunity to develop a
increase cellular proliferation and survival [31]. more personalized approach to stem cell therapy for
Furthermore, Sanada and colleagues [32] have shown heart disease. It is evident that we are on the right
in a mouse model that older hearts have more quies- path of discovery in this field, and we should, there-
1
cent c-kit cardiac stem cells than younger hearts, but fore, have the fortitude to continue. As Shakespeare
thatstemcellfactorcanbeusedtostimulatethesecells also admonished, let us not “lose the good we oft
andeffectively reverse aging cardiomyopathy. might win, by fearing to attempt.”‡
Studies have also indicated that the efficacy of stem
cell treatments can possibly be enhanced by using spe-
GENE THERAPY
cific cell combinations. In a porcine model of MI,
Williams and colleagues [33] showed that a combina-
1
tion of mesenchymal and c-kit stem cells improved The other area in which clinical trials are a critical
LV function and reduced infarct size significantly method to enhance our understanding of the mechan-
more than either cell type did alone. The encouraging isms involved in native tissue repair is targeted gene
results with cardiosphere-derived cells in patients with therapy. There is strong preclinical evidence that the
ischemic cardiomyopathy also suggest that using a majormechanismbywhichstemcellsaffecttheirbene-
combination of stem cells may be more effective than fit is via paracrine release of a variety of trophic sub-
using a singletype ofstem cell[4,5]. stances(e.g.SDF-1)thatthenactivateresidentstemcells
Therefore, clinical trials assessing the use of select [34,35]. This hypothesis was confirmed by the work of
adult stem cells for treating patients with ischemic car- Dzau [34] who showed that the supernatant from stem
diomyopathies have produced encouraging results cellsinculturewasaseffectiveastransplantationofthe
that suggest these therapies are safe and may poten- cells alone. This has led to the hypothesis that delivery
tially improve clinical outcomes, including LV func- of sufficient quantities of targeted genes to the area of
tion, infarct size, and the occurrence of future adverse injury or dysfunction could potentially be as effective
clinical events. However, the studies performed to asstemcelldeliveryindrivingnativetissuerepair.
date have been relatively small, and the follow-up for Preclinical research has identified several types of
these studies has been limited to only a few months to potential target genes, which can be delivered as syn-
years. Furthermore, when designing future studies, thesized human genes and cause no immune stimula-
clinicians should continue to build on what is now tion, and therefore have a minimal risk equivalent to
known about stem cell biology and should try new autologous stem cells. Some of the very first trials of
approaches based on this information, such as using regenerativemedicine for cardiovasculardisease tested
‡MeasureforMeasure,ActI,sc.4,lines435(cid:3)436.