Full Text HL-93-019


NIH GUIDE, Volume 22, Number 36, October 8, 1993

RFA:  HL-93-019

P.T. 34

  Cardiovascular Diseases 
  Biology, Cellular 

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:   December 14, 1993
Application Receipt Date:  January 13, 1994


The objective of this Request for Applications (RFA) is to stimulate
interdisciplinary research leading to the development of implanted
cardiovascular devices lined with genetically modified cells.  These
cell-lined devices would be capable of (1) secreting substances into
the local microenvironment that would enhance the biocompatibility of
the device or (2) serving as an "organoid" (a hybrid organ composed
of a biomaterial lattice coated with secretory cells) that would
function as a source for chronic systemic delivery of agents with
desirable cardiovascular actions.  This research may lead to reduced
complications with the use of heart valves, vascular grafts, stents,
and circulatory support systems and improved treatment of disorders
such as atherosclerosis, diabetes, and hypertension.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  The RFA,
Genetically Enhanced Cardiovascular Implants, is related to the
priority area of heart disease and stroke.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).


Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State or local
governments, and eligible agencies of the Federal government.
Applications from foreign organizations should be limited to three
years. Applications from minority individuals and women are


This RFA will use the National Institutes of Health (NIH) individual
research grant (R01).  Responsibility for the planning, direction,
and execution of the proposed project will be solely that of the
applicant.  The total project period for applications submitted in
response to the present RFA may not exceed five years.  The
anticipated award date is August 1, 1994.  Because the nature and
scope of the research proposed in response to this RFA may vary, it
is anticipated that the size of the awards will vary also.  This RFA
is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary
peer review procedures.


It is anticipated that, for FY 94, approximately $750,000 will be
available for this RFA from the Advanced Biomaterials program of the
Federal Coordinating Council for Science, Engineering, and Technology
(FCCSET) initiative, and that four grants will be awarded under this
program.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plan of the NHLBI,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.  Administrative adjustments in project period
and/or amount of support may be required at the time of the award.


Biocompatibility problems are encountered with the use of implanted
cardiovascular devices such as artificial hearts, ventricular assist
devices, heart valves, small diameter vascular grafts, and stents.
The problems are exacerbated by long implantation times.  Most of the
patients in whom an artificial heart has been implanted for more than
90 days developed thromboembolic and infectious complications related
to the implant.  There is a lesser but significant incidence of these
complications with other devices such as prosthetic heart valves and
vascular grafts.

Recent experimental studies indicate the feasibility of developing an
"organoid" consisting of a biomaterial lattice coated with
genetically engineered cells.  Further studies are needed to
determine the function and control of such an organoid over prolonged
periods of time.  Although not yet known, it is feasible that this
approach could lead to new modes of prevention and treatment of
atherosclerosis, hypertension, diabetes and other conditions.
Development of such modalities could introduce new therapeutic
options for non-cardiovascular disorders as well.

Implants incorporating genetically modified cells have the potential
for continuous delivery of effective concentrations of proteins of
therapeutic interest synthesized by the cells.  Thus, the potential
exists for using these implants in two ways.

1.  The biocompatibility problems of implants may be addressed by use
of cells which secrete molecules capable of locally controlling or
preventing thrombosis and intimal hyperplasia.

2.  A different set of opportunities exists for delivery of
therapeutic agents for treatment of conditions not directly related
to the implanted device.  For example, an organoid comprising
genetically modified cells on a polymer matrix might be used to treat
various cardiovascular disorders by delivery of antithrombotic,
thrombolytic, antiproliferative, vasoactive, angiogenic, or other

In recent years, endothelial cells have been the subject of a great
deal of research activity.  Some of this activity has focused on
methods for seeding vascular grafts with an endothelial cell
monolayer, and considerable progress has been reported.  Autologous
endothelial cells can be isolated from microvessels in adipose tissue
and attached to the luminal surface of vascular grafts prior to
implantation in a clinical setting.  This approach has potential for
improving the biocompatibility of various types of vascular implants.

Recent work has shown the feasibility of using endothelial cells as
targets for gene transfer.  Canine, porcine, ovine, rabbit and human
endothelial cells have been transduced successfully, as demonstrated
by the use of marker genes. In the canine model, the genetically
altered cells have been shown to persist when used to seed Dacron
grafts in the donor animal.  Genetically altered porcine endothelial
cells will retain their function when seeded on a native artery that
had previously been deendothelialized by balloon angioplasty.

The use of intravascular stents is frequently complicated by
thrombosis and stenosis due to intimal proliferation. Stainless steel
stents have been seeded with endothelial cells in which the gene for
tissue-type plasminogen activator (t-PA) has been inserted, using the
technique of retroviral-mediated gene transfer.  Increased expression
of t-PA by the genetically modified cells has been demonstrated in
these studies.

Another promising method to introduce genetically altered cells into
a patient's body involves creation of an "organoid" or hybrid organ.
In this approach, angiogenesis is induced along fine polymer fibers
by coating them with heparin-binding growth factor 1 and collagen
prior to implantation.  The result is a synthetic organ containing
vascular lumina among nonvascular structures.  The vascular system of
the implant is continuous with that of the host.  By this technique
it was demonstrated that homozygous Gunn rats, congenitally deficient
UDP-glucuronosyltransferase for the conjugation of bilirubin,
maintained a drop in serum bilirubin from a baseline of > 9mg/dl to
<3mg/dl for at least four months following injection of hepatocytes
from normal Wistar rats into an intraperitoneal expanded
polytetrafluoroethylene fiber network.  This approach may permit
prolonged delivery of products of genetically altered cells.

While the above studies demonstrate the feasibility of the organoid
approach, further progress will require close collaboration between
cell and molecular biologists, materials scientists, and
bioengineers.  A major objective of this initiative is to facilitate
and foster such interactions in order to gain an improved
understanding of the basic processes of organoid development and

Applications responsive to this request should demonstrate expertise
in both biomedical sciences and biomaterials science.  The focus of
the work under this initiative should be primarily on implants with
cardiovascular applications.  Either the local implant or the
systemic organoid approach may be investigated.  It is expected that
most applications will involve animal models as well as cell
cultures.  In vivo studies on human subjects will not be supported,
although in vitro studies with human cells are acceptable.

Suggested areas of research include, but are not limited to, the

o  Studying genetic modification of endothelial or other cells for
the production of recombinant proteins with desired therapeutic
effects and investigating mechanisms of control of expression of
recombinant genes.

o  Investigating the long-term function of genetically modified cells
seeded on stents, prosthetic vascular grafts, mechanical heart
valves, or other implants.

o  Studying the parameters that affect the functions of organoids for
cardiovascular applications.  These may include the chemical nature
of the polymer, surface receptor mechanisms on the polymer, the
effect of cell adhesion molecules or growth factors coated on the
polymer fibers, configuration of the polymer network, and the
techniques of implantation.  Developing methods for assessing
function and structure of the organoid during long-term implantation.

o  Defining the conditions under which vascularization of the
organoid is reproducible, complete, and long- lasting.

o  Investigating failure modes: immunologic rejection if non-
autologous cells are used), decline or cessation of expression,
malignant change, effects on other genes.  Developing strategies for
responding to such events.


Prospective applicants are asked to submit, by December 14, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.  Although a letter of intent
is not required, is not binding, and does not enter into the review
of subsequent applications, the information that it contains is
helpful in planning for the review of applications.  It allows NHLBI
staff to estimate the potential review workload and to avoid conflict
of interest in the review.

The letter of intent is to be sent to:

Dr. Matthew Starr
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553A
Bethesda, MD  20892
Telephone:  (301) 594-7448
FAX:  (301) 594-7407


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/710-0267; and from the NIH program administrator listed

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, the RFA title and number must be typed on
line 2a of the face page of the application form and the YES box must
be marked.

Send or deliver a signed, typewritten original of the application,
including the checklist, and three signed photocopies, in one package

Division of Research Grants
National Institutes of Health
Westwood Building, Room 449
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to Dr. Matthew Starr at the address listed under

Applications must be received by January 13, 1994.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this announcement that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The DRG will not
accept any application that is essentially the same as one already
reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NHLBI.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NHLBI staff will contact
the applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.

Applications may be triaged by an NHLBI peer review group on the
basis of relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be non-competitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications judged to be competitive
will undergo further scientific merit review.  Those applications
that are complete and responsive will be evaluated in accordance with
the criteria stated below for scientific/technical merit by an
appropriate peer review group convened by the NHLBI.  The second
level of review will be provided by the National Heart, Lung, and
Blood Advisory Council.  Although multidisciplinary approaches are
encouraged, it is not the intent of this announcement to solicit
applications for large studies that would encompass a variety of
independent projects, i.e., program projects.

Review criteria to be considered in the evaluation of applications
will include:

o  Scientific, technical, or medical significance and originality of
proposed research;

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  Qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  Availability of the resources necessary to perform the research;

o  Appropriateness of the proposed budget and duration in relation to
the proposed research;

Additional scientific/technical merit criteria specific to the
objectives of the RFA must be included.


The anticipated date of award is August 1, 1994.  Criteria for making
awards will include priority score, availability of funds, and
programmatic priorities.


Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Paul Didisheim
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
7550 Wisconsin Avenue
Federal Building, Room 312
Bethesda, MD  20892
Telephone:  (301) 496-1586
FAX:  (301) 480-6282

Direct inquiries regarding fiscal and administrative matters to:

Mr. William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 594-7458
FAX:  (301) 594-7492


This program is described in the Catalog of Federal Domestic
Assistance No. 93.837.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency


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