REQUEST FOR INFORMATION ON THE TRANSLATION OF CELL-BASED THERAPIES FOR 
CARDIOVASCULAR DISEASES

RELEASE DATE:  April 9, 2004

NOTICE:  NOT-HL-04-108

National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov/index.htm)

Response Due Date:  June 1, 2004

PURPOSE

The NHLBI is soliciting comments and ideas on approaches to translate and 
implement cell-based therapies for the treatment of cardiovascular diseases.

BACKGROUND

Cardiovascular disease, including hypertensive disease and myocardial 
infarction, leads to loss of cardiac tissue through apoptotic and necrotic cell 
death. The remaining myocytes are unable to reconstitute the lost tissue, and 
the diseased heart deteriorates functionally with time.  Current options for 
treating these conditions suffer from limitations and are primarily directed at 
limiting disease progression rather than repair and restoration of healthy 
tissue and function. In light of the limited efficacy and co-morbidity of these 
current treatment options, alternative, additional long-term therapeutic 
strategies are needed. Cardiac repair is one potential new therapeutic option 
for repairing damage to the heart resulting from myocardial infarction or 
ventricular remodeling.  Through cellular therapies, the concept of "growing" 
heart muscle and vascular tissue and manipulating the myocardial cellular 
environment may revolutionize the approach to treating heart disease.  

Recent studies suggest that stem cells resident within the bone marrow or 
peripheral blood can be recruited to the injured heart.  Two of the most widely 
used cell types for cardiac repair today are skeletal muscle-derived 
progenitors, or myoblasts, and bone marrow-derived progenitors.  Both cell 
types share advantages over other cells proposed for cardiac repair in that 
they are readily available, autologous, and more easily expanded in vitro.  
Adding to this mix is accumulating evidence that the heart contains resident 
stem cells that can be induced to develop into cardiac muscle and vascular 
tissue.  

Transplantation of both skeletal myoblasts and bone marrow-derived stem cells 
into the region of infarcted myocardium results in improved myocardial function 
in both the murine and porcine infarct models.  The injection of stem cells and 
bone marrow stimulating cytokines in model systems produces functional cardiac 
benefit.  Studies employing ischemic limb models indicate that cell therapy with 
endothelial progenitor cells can successfully promote neovascularization of 
ischemic tissues.  A similar strategy applied to a model of myocardial ischemia 
in the nude rat demonstrates that transplanted human endothelial progenitor 
cells localize to areas of myocardial neovascularization, differentiate into 
mature endothelial cells, enhance neovascularization and are associated with 
preserved left ventricular function and diminished myocardial fibrosis.  Genetic 
modification of progenitor cells prior to transplantation has also been used to 
enhance survival of the implanted cells.  However, the issues surrounding 
autologous cell-based therapy for cardiovascular disease are substantial.  For 
muscle repair, cells must incorporate themselves into the heart, survive, 
mature, and electromechanically couple and ultimately increase contractile 
function.  In terms of stimulating the formation of new blood vessels to 
increase blood flow to affected regions, cells must develop vascular beds 
complete with smooth muscle and endothelium that connects and conducts blood 
flow.  In order for cell therapy to be widely clinically applicable, the optimal 
cell has to be compatible both mechanically and electrically with the host 
myocardium. 

An additional cell-based therapy research area which shows promise is the 
mobilization of progenitor cells in vivo using cytokines, and subsequent homing 
of the mobilized cells to damaged myocardium.  Injection of cytokines and other 
chemotactic molecules into the heart also shows promise for enhancing homing of 
progenitor cells mobilized in vivo or injected into the vasculature.
 
The concept of transplanting autologous cells into a damaged heart has received 
significant attention, both in scientific circles and the popular press.  The 
most exciting and promising clinical studies to date have evaluated autologous 
stem cell transplantation soon after acute myocardial infarction.  Ongoing 
clinical trials in Europe and elsewhere are examining the safety and efficacy of 
autologous skeletal myoblast transplantation in patients as an adjunct to 
coronary artery bypass surgery.  Published studies have used bone marrow or 
peripheral circulating progenitor cells that were injected down the 
infarct-related artery and a randomized controlled trial has shown improvement 
of left ventricular ejection fraction with bone marrow cell transfer into the 
infarct related artery.  

The NHLBI has launched a number of programs to foster research on basic, 
pre-clinical studies of stem cells.  However, the scientific community and the 
public are now looking to apply these fundamental basic science observations to 
the treatment of cardiac diseases.  Careful consideration and direction are 
needed to safely and effectively translate cell-based therapies into medical 
practice. 

INFORMATION REQUESTED

The NHLBI seeks your help in identifying (a) the major opportunities to develop 
and apply cell-based therapies to heart disease; (b) the critical needs to 
enable progress, and the barriers that may inhibit it; and (c) practical and 
effective ways to meet the needs, overcome the barriers, and take full advantage 
of the opportunities.  Your thoughts, ideas, and suggestions will be used to 
help guide future Institute activities designed to expedite the translation of 
cell-based therapies the treatment of cardiovascular disease and efforts to 
improve patient care. Respondents are asked to comment on one or more of the 
issues listed below, but should not feel compelled to address all of them.

1.   Please identify the major needs for, and barriers to, translating cell-
based therapies to cardiovascular disease and medicine.  Specific suggestions 
concerning steps or requirements that must be met in order to translate cell-
based therapies for cardiovascular disease would be helpful. 

2.   Please suggest approaches the NHLBI can take to meet the needs, overcome 
the barriers, and take full advantage of the opportunities.  Any specific 
suggestions regarding expertise, capabilities, and resources needed would be 
valuable. 

3.   Please comment on the selection of cell type to be used for cell-based 
therapies for cardiovascular disease.  Provide specific suggestions regarding 
the use of autologous versus allogeneic cells, and the need for isolation, 
purification, and characterization of the cells. 

4.   Please consider and comment on safety and regulatory issues that are likely 
to be encountered in translating cell-based therapies.  Please include ideas on 
how these issues can be addressed.

5.   We would appreciate any additional views or opinions that you think would 
be useful.

RESPONSE AND PROCESS 

Responses in any of the areas are welcome; respondents should not feel compelled 
to address all items.  Please respond no later than June 1, 2004.  Responses 
will be compiled and shared with our advisory committees.  We look forward to 
your thoughts, opinions, and suggestions and hope you will share this document 
with your colleagues.  Thank you very much for your help. 

To respond, please link to the online form in the NHLBI Grants and Contracts 
page under Funding, Training and Policies section of the Information for 
Researchers area on the NHLBI Home Page 
http://www.nhlbi.nih.gov/funding/inits/rfi_cellbased.htm), or 
send a letter, fax, or e-mail to the following address: 

NHLBI/DHVD Data Coordinator 
c/o Ms. Tawanna Meadows
Two Rockledge Centre
6701 Rockledge Drive
Suite 9044 , MSC 7940
Bethesda, MD 20892-7940
Telephone: (301) 435-1802
FAX: (301) 480-1335
E-mail: DHVDdata@nhlbi.nih.gov

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