and Human Services (HHS)
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: [email protected]
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