Full Text HL-96-019
NIH GUIDE, Volume 25, Number 31, September 20, 1996
RFA:  HL-96-019


National Heart, Lung, and Blood Institute
Letter of Intent Receipt Date:  January 10, 1997
Application Receipt Date:  February 13, 1997
The National Heart, Lung, and Blood Institute (NHLBI) invites Program
Project grant applications for support of research efforts to advance
gene transfer technology and its potential application to
cardiovascular, pulmonary, and hematologic diseases.  The overall
objective of this program is to foster research that will provide the
basic science foundation necessary for gene transfer technology and
its application to somatic gene transfer by:(1)promoting the alliance
of a critical mass of talented and dedicated investigators with
expertise in the diverse areas essential for successful
implementation of this research program; (2)providing the
infrastructure needed to establish the collaboration of experts in a
wide-ranging number of scientific areas; and (3)funding innovative
pilot and feasibility studies to attract new and established
investigators into the field of gene transfer for cardiovascular,
pulmonary, and hematologic diseases.
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.  This request
for applications (RFA), "Fundamental Biological Principles for Gene
transfer for Cardiovascular, Pulmonary, and Hematologic Diseases", is
related to the priority area of Heart Disease and Stroke, Diabetes
and Chronic Disabling Diseases, and Maternal and Infant Health.
Methodologies and biotechnological advances resulting from these
studies may also be applicable to the priority areas of Cancer, and
Food and Drug Safety. 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. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, D.C. 20402-9325 (telephone 202-783-3283).
Applications may be submitted by domestic, for-profit and nonprofit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal government.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
All current policies and requirements that govern the research grant
programs of the NIH will apply to grants awarded under this RFA.
Awards under this announcement will not be made to foreign
This RFA will use the NIH Program Project grant (P01) mechanism of
support (containing research projects and the requisite shared
infrastructural resources (cores) as subcomponents under the aegis of
the parent grant).  A Program Project grant is for the support of a
broadly-based multidisciplinary or multifaceted research program that
has a specific major objective or central theme.  The award may
support research components and core functions. Collectively, these
components should demonstrate essential elements of unity and
interdependence and result in a greater contribution to program goals
than if each activity were pursued individually.
Applications must be prepared and awards will be made according to
NHLBI Program Project policies.  NHLBI Guidelines for the preparation
of the Program Project Grant applications may be obtained from Dr. C.
James Scheirer at the address listed under LETTER OF INTENT.
Applicants are expected to furnish their own estimates of time
required to achieve the objectives of the proposed research project.
Up to 5 years of support may be requested.
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 support for
this program will begin in September 1997.  Administrative
adjustments in project period and/or amount may be required at the
time of the award.
It is anticipated that for fiscal year 1997, approximately $5,130,000
total costs will be available for the first year of support for this
initiative.  Applicants may request up to $1,140,000 direct costs,
not including indirect costs for collaborating institutions, in the
first year with a maximum increase of no more than 4 percent in each
additional year requested.  Award of grants pursuant to this RFA is
contingent upon receipt of funds for this purpose.  It is anticipated
that three program project grants will be awarded under this program.
The specific number to be funded will, however, depend on the merit
and scope of the applications received and on the availability of
Pilot and feasibility studies may be submitted to pursue promising
but untested methodologies or highly novel research.  Funding for
such projects is included in the $1,140,000 direct cost cap.  Each
pilot and feasibility project may request up to $60,000 in total
costs per year for a maximum of two years.  New projects, subjected
to the same dollar and time limits, may be proposed to replace those
that terminate.  At any one time, a maximum of 3 pilot and
feasibility projects will be allowed per program project research
grant.  The mechanism for selecting and reviewing initial and
subsequent pilot/feasibility projects during the 5 year tenure of
this program is detailed in the special guidelines governing this
program, available from the program administrators listed at the end
of this announcement.
Equipment is included in the budget limitation.  However, requests
for special equipment that cause an application to exceed this limit
may be permitted on a case-by-case basis following staff
consultation.  Such equipment requires strong justification.  Final
decisions will depend on the nature of the justification and the
availability of funds.
If a grant application includes research activities that involve
institutions other than the grantee institution, the program is
considered a consortium effort.  Such activities may be included in a
Program Project grant application, but it is imperative that a
consortium application be prepared so that the programmatic, fiscal,
and administrative considerations are explained fully.  In addition,
NHLBI requires that at least half of both the subprojects and cores
submitted and funded be in the applicant institution.
The published policy governing consortia is available in the business
offices of institutions that are eligible for Federal grants-in-aid.
Consult the latest published policy governing consortia before
developing the application.
If clarification of the policy is needed, contact William Darby,
(301)435- 0177.  Applicants for Program Project grants should clearly
describe the interactions of the participants and the integration of
the consortium project(s) with those of the parent institution,
because synergism and cohesiveness can be diminished when projects
are located outside the group at the parent institution.  Indirect
costs paid as part of a consortium agreement are excluded from the
limit on the amount of direct costs that can be requested.
A key ingredient for the success of this program is the
multidisciplinary collaboration of investigators skilled in pursuing
basic science principles in areas such as gene expression with
researchers who are skilled in the application of such principles to
gene transfer for cardiovascular, pulmonary and hematologic diseases.
Hence, one of the objectives of this program is to foster the
alliance of a critical mass of talented and dedicated investigators
with expertise in the diverse areas essential for successful
implementation of this research program.  This intensive,
multi-disciplinary enterprise will require substantial interaction
and coordination among individuals skilled in molecular biology,
virology, developmental biology, cellular biology, bioengineering,
pathology, genetics, biochemistry, physiology and other disciplines
dealing with biologic mechanisms and health and diseases.
Program Project guidelines require that at least half of both the
subprojects and cores submitted and funded be in the applicant
Another important objective of this initiative is to provide the
infrastructure needed to establish the collaboration of experts in a
wide-ranging number of scientific areas.  In order to provide the
appropriate infrastructure, funds may be utilized to support core
resources as shared facilities.
These "shared" resources form the structural foundation for the areas
of scientific need and are an important goal of this program.  Rather
than being purely service oriented cores for performance of routine
functions, there may be a need for some of these cores to be involved
in technological developments, such as in the area of vectors.  These
"shared" infrastructural resources must be flexible enough to meet
the needs of the constantly evolving science.  As such, the
investigators will be required to provide yearly progress reports
delineating the functions of these cores for the previous and future
project periods to assure that the cores are meeting the scientific
and technical needs requisite for advancing gene therapy.
An important goal of this program is to attract new and established
investigators into the field of gene therapy by providing access to
critical technologies (in the form of shared resources described
above) and funds to pursue innovative pilot/feasibility studies.
Pilot and feasibility studies, when combined with appropriate core
support, will provide established investigators who have not
previously worked in gene transfer and new young investigators with
state-of-the-art core technologies to be competitive in the field.
In addition, pilot and feasibility studies will allow investigators
to pursue promising but untested methodologies or highly novel,
research avenues that may offer significant results and insight.
However, funds for these pilot/feasibility studies are not intended
to support or supplement ongoing funded research of an investigator.
It is anticipated that by providing preliminary results and
establishing feasibility data, these pilot studies will lead to new
research proposals in the area of gene transfer as it will relate to
prevention and treatment of cardiovascular, pulmonary and hematologic
Applicants are requested to propose a Pilot and Feasibility Committee
that will be responsible for developing and selecting those projects
most likely to aid progress in achieving successful gene transfer.
Each pilot and feasibility project may request up to $60,000 in total
costs per year for a maximum of two years.  New projects, subjected
to the same dollar and time limits, may be proposed to replace those
that terminate.  At any one time, a maximum of 3 pilot and
feasibility projects will be allowed per program project research
The introduction of genetic material into human cells with successful
expression of the inserted gene is a historic technological advance.
It allows the development of novel strategies for prevention control,
and treatment of disease through the use of gene transfer.
Conceptually, gene transfer can be used to correct or replace
defective genes. Current approaches for gene transfer attempt to
introduce genes in addition to the endogenous genome in an effort to
restore or enhance normal cellular activities or to confer new
cellular activities.  This approach does not attempt to correct
resident, nonfunctional mutant genes.  The introduction of genetic
material to prevent the expression of disease-causing genes is
another gene transfer approach.
At the present time, however, molecular genetic interventions for
cardiovascular, pulmonary, and hematologic diseases face many
difficult technical hurdles.  Critical basic science issues must be
addressed prior to transfer of this technology to the clinic.
Expanded and new research efforts are necessary to develop the basic
tasks involved in gene transfer, such as insuring regulated, stable
and cell-specific expression of transferred genes in target cells,
developing efficient gene transfer delivery systems, and producing
animal models of cardiovascular, pulmonary, and hematologic disease
in order to develop and test novel therapeutic approaches.  In
addition, gene transfer research affords the opportunity to further
the understanding of the genetic components of single gene and
multifactorial gene diseases.  Hence, it is critical to facilitate
research efforts that include molecular, cellular, genetic and
preclinical studies to advance gene transfer technology and its
application to a wide range of cardiovascular, pulmonary, and
hematologic diseases.
The potential of gene transfer to treat cardiovascular diseases is
substantial.  However, there are unique features of cardiovascular
diseases that require special gene transfer approaches.  For example,
the focal nature of coronary artery disease and restenosis may
require direct delivery of therapeutic genetic material to specific
myocardial or vascular sites.  Additional challenges encountered with
cardiovascular cells include the non-dividing nature of some cell
types, such as heart myocytes.  Strategies for other cardiovascular
diseases might include gene transfer to:  treat myocardial ischemia
by promoting collateral circulation; prevent vascular smooth muscle
proliferation following angioplasty; and prevent cardiac
transplantation rejection by altering the cell surface properties to
deter an immune response.
There are many opportunities for application of gene transfer
techniques to prevention and treatment of pulmonary disorders.
Although there have been several promising advances in the use of
gene transfer approaches for cystic fibrosis, major barriers for this
and other pulmonary diseases to further progress exist.  Mechanisms
that underlie the immune response to viral vectors need to be
elucidated.  The development and characterization of more efficient
gene transfer delivery systems need to be established.  The use of
gene transfer to ameliorate or prevent inflammatory lung disorders
such as ARDS and asthma is just beginning to be explored.  Gene
transfer to the pulmonary vasculature is also largely unexplored.
The role of this approach to treating pulmonary thrombosis, pulmonary
hypertension, or other conditions needs to be evaluated.
Bronchopulmonary dysplasia, pulmonary fibrosis, and chronic
obstructive pulmonary disease are other potential targets for the use
of gene transfer.
Many of the problems and needs relevant to gene transfer in the
cardiovascular and pulmonary areas are generally applicable to
hematologic genetic diseases, such as hemophilia, sickle cell
disease, and thalassemia.  Choice of the appropriate target cell
ranges from important to critical for hematologic disorders.  In the
case of hemophilia, the normal site of production of factors VIII and
IX is believed to be the liver; however, other target cells such as
myoblasts and fibroblasts have been used in preliminary experiments.
Also critical is access of the secreted gene product to the
circulation.  Studies of mechanisms of development and suppression of
immunity to newly expressed gene products will also be an important
issue.  Thus, although much progress has been made, many basic issues
crucial to clinical success remain.
In order for key advances to take place in the needs outlined above,
there are critical biological tasks that must be solved.  Hence, the
focus of this initiative will be on the fundamental questions related
to applications of gene transfer technology for use in the
cardiovascular, pulmonary, and hematologic systems.  Clinical gene
transfer trials are beyond the scope of this initiative.
Research needs include:
Gene Expression:  It is important to understand the underlying
mechanisms that determine how the transferred gene is expressed in
sufficient amounts in the physiologically correct manner.  Too much,
too little, or inappropriately timed expression may be harmful.  More
information is also needed about secretion of expressed proteins into
appropriate compartments or into the circulation.  An understanding
of cell specific and tissue specific gene expression, as it relates
to gene transfer, is required.  An understanding of the biological
consequences of recombinant gene expression needs to be gained.
Studies aimed at examining the effect of gene transfer on the normal
biological function of the target cell, tissue and animal will be
Gene Delivery and Transfer:  Current techniques for inserting genes
into target cells must be improved and new ones need to be developed
to insure efficient gene transfer. Studies might involve viral,
physical, chemical and fusion techniques to develop improved
packaging and more effective gene delivery.  Recent developments in
controlled drug release technology, including the use of
biodegradable polymers in the form of layers or microspheres and
containing the desired gene, may be applicable to gene delivery.
Relevant issues of immunity, safety, efficacy, and production require
exploration.  Research aimed at designing methods to insure
cell-specific and stable long-term expression of transferred genes is
essential. Development of techniques to target genes to specific
chromosomal locations by homologous recombination need further
Target Cells:  There is a need to identify appropriate target cell
populations for successful gene transfer treatment of cardiovascular,
pulmonary, and hematologic diseases.  Identification of stem cell
populations, if appropriate, would be encouraged.  In addition,
methods for improved cell purification and routine isolation of
highly purified cell populations, as have been developed for bone
marrow cells, need to be established for other cells. Improved cell
culture techniques for growth and maintenance of nontransformed cells
are necessary and may involve the identification and use of cytokines
and receptors that regulate cell growth.  Efforts need to be directed
toward isolating, purifying and maintaining cardiac and vascular
myocytes, endothelial cells and cells in other organs that
participate in cardiovascular, pulmonary, and hematologic disorders.
Disease Pathophysiology:  Basic studies in disease pathophysiology
are critical to the eventual success of gene therapy.  Such studies
can lead to a better definition of the important target cell(s) and
to more effective designs of therapeutic approaches.
Cellular and Humoral Immunity:  The role of cellular and humoral
immunity in the gene transfer process needs clarification.
Interventions to suppress the immune response are in need of
exploration, as well as the development of novel vector systems that
selectively minimize or repress the immune response of the host
Model Systems:  Model systems (in vivo and in vitro) need to be
developed and explored to assess the safety and efficacy of viral and
nonviral vector systems.  Animal models of human diseases allow
researchers to design and evaluate gene transfer strategies that
cannot be assessed in humans. Naturally occurring animal models that
mimic human diseases occur occasionally.  It is now possible,
however, to use transgenic and gene targeting approaches to create
and utilize animal models of human diseases.  Hence, the generation
and use of genetically altered animal models to develop and test gene
transfer approaches needs to be encouraged.
Clinical Applications:  While funding for clinical gene therapy
trials is beyond the scope of this initiative, the development of
programs which will lead to cardiovascular, pulmonary, and
hematologic gene transfer trials is encouraged.  This might include
the identification of candidate therapeutic genes; development of
vector systems to optimize gene delivery and expression in target
cells; and to test the safety and efficiency of gene expression in
animal models.
Upon initiation of the program, the NHLBI will sponsor periodic
meetings to encourage exchange of information among investigators who
participate in this program.  In the budget for the grant
application, applicants should request travel funds for a 1-day
meeting each year, most likely to be held in Bethesda, Maryland.
Applicants should also include a statement in their applications
indicating their willingness to participate in these meetings.
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), that
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.
All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513)and reprinted
in the NIH Guide to Grants and Contracts, Volume 23, Number 11, March
18, 1994.  Investigators also may obtain copies of the policy from
the program staff listed under INQUIRIES.  Program staff may also
provide additional relevant information concerning the policy.
Prospective applicants are asked to submit, by January 10, 1997, 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 a subsequent application, the information that it contains allows
staff to estimate the potential review workload and to avoid conflict
of interest in the review.
The letter of intent is to be mailed, or faxed, to:
Dr. C. James Scheirer Chief,
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301)435-0266
FAX:  (301)480-3541
Email:  James_Scheirer@NIH.GOV
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
from the Grants Information Office, Office of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267,
email:  ASKNIH@odrockm1.od.nih.gov; and from the program staff listed
Special program project guidelines have been developed to meet the
special features and needs of this RFA program and must be used in
applying for these grants.  These guidelines can be obtained from Dr.
Sonia Skarlatos at the address listed under INQUIRIES.
The RFA label found in the PHS 398 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.
Submit a signed, typewritten original of the application and three
signed, photocopies, in one package to:
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
At the time of submission, two additional copies of the application
must be sent to Dr. C. James Scheirer, at the same address given
above in the section on LETTER OF INTENT.
Applications must be received by February 13, 1997.  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 RFA that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  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 for responsiveness by the NHLBI.  Incomplete applications will be
returned to the applicant without further consideration.  If NHLBI
staff find that the application is not responsive to the RFA, it will
be returned without further consideration.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened in accordance with NIH peer review procedures.
As part of the initial merit review, all applications will receive a
written critique and undergo a triage process in which only those
applications deemed to have the highest scientific merit, generally
the top half of applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
National Heart, Lung, and Blood Advisory Council. The NIH will
withdraw from further competition those applications judged to be
noncompetitive for award and notify the applicant Principal
Investigator and institutional official.
The personnel category will be reviewed for appropriate staffing
based on the requested percent effort and any changes requested in
future years.  The total budget request will be reviewed for
consistency with the proposed methods and specific aims.  The
duration of support will be reviewed to determine if it is
appropriate to ensure successful completion of the recommended scope
of the project.
Other review criteria 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 appropriateness and design of the shared core facilities proposed
to provide infrastructural support to the major scientific components
of the gene therapy effort, including plans to monitor their
performance and ability to meet changing scientific needs
o adequacy and availability of the resources and facilities to
support proposed clinical and basic research
o qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research originality of proposed research
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research originality of proposed research
o adequacy of internal and external procedures for monitoring and
evaluating the proposed research and for providing on-going quality
control and scientific review
o scientific merit of any proposed pilot/feasibility studies and the
quality of the internal and external review mechanism established by
the parent institution to evaluate the scientific merit of the
initial and subsequently selected pilot/feasibility projects,
including development of a detailed plan for maintaining oversight
and review of on-going pilot/feasibility studies and for providing
written documentation of these actions, copies of which will be
forwarded to the NHLBI Program Administrators
o commitment of the grantee institution and any cooperating
institution to the program, and the appropriateness of its resources
and policies for the administration of a research program of the type
proposed; and the appropriateness of the requested budget to the work
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:  quality of the proposed project as determined by peer
review, availability of funds, and program priority.
Letter of Intent Receipt Date:    January 10, 1997
Application Receipt Date:          February 13, 1997
Initial Review:                    April/May 1997
Review by NHLBI Advisory Council:  September 1997
Anticipated Award Date:            September 30, 1997
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues and requests for the
Program Project Guidelines to:
Sonia Skarlatos, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10186
Bethesda, MD  20892-7956
Telephone:  (301)435-0550
FAX:  (301) 480-2848
Susan Banks-Schlegel, Ph.D.
Division of Lung Diseases
National Heart, Lung and Blood Diseases
6701 Rockledge Drive, Suite 10220
Bethesda, MD  20892-7952
Telephone:  (301)435-0202
FAX:  (301)435-3557
Carol Letendre, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung and Blood Diseases
6701 Rockledge Drive, Suite 10162
Bethesda, MD  20892-7950
Telephone:  (301) 435-0080
FAX:  (301) 435-0867
Direct inquiries regarding fiscal matters to:
Mr. William Darby
Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Center
6701 Rockledge Drive, Suite 7128
Bethesda, MD  20892-7128
Telephone:  (301) 435-0177
FAX:  (301) 480-3310
Email:  William_Darby@NIH.GOV
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
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.

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