Full Text HL-93-08

GENE THERAPY APPROACHES FOR CYSTIC FIBROSIS AND OTHER HEART, LUNG,
AND BLOOD DISEASES

NIH GUIDE, Volume 21, Number 39, October 30, 1992

RFA:  HL-93-08-L

P.T. 34

Keywords: 
  Gene Therapy+ 
  Cardiovascular Diseases 
  Pulmonary Diseases 
  Biomedical Research, Multidiscipl 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  January 25, 1993
Application Receipt Date:  April 22, 1993

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites grant
applications for support of research to develop approaches to gene
therapy of diseases of interest to the NHLBI, with special emphasis
on cystic fibrosis (CF). The overall objectives of this program are
to advance gene therapy for CF and other cardiovascular, lung, and
blood diseases by promoting intra- and inter- institutional
collaborations, developing infrastructural resources, and fostering
the entry of young and established investigators into the field of
gene therapy research, as well as to promote novel, innovative pilot
and feasibility studies by established gene therapy investigators.

The special emphasis of this initiative is to promote
multidisciplinary basic, pre-clinical, and clinical research
approaches to gene therapy for CF, aimed ultimately at a cure for the
devastating pulmonary manifestations of the disease, which are the
major cause of CF mortality.  Because many of the basic and clinical
science issues relevant to gene therapy for CF are identical to those
of other heart, lung, and blood diseases, grant applications in
response to this request for application (RFA) must include a
commitment and plan to share core facilities with investigators
exploring gene therapy for other cardiovascular, lung, and blood
diseases.

HEALTHY PEOPLE 2000

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 RFA,
Gene Therapy Approaches for Cystic Fibrosis and Other Heart, Lung,
and Blood Diseases, is related to the priority area of chronic
disabling conditions.  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, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and nonprofit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of state and local governments, and
eligible agencies of the Federal government.  Applications from
minority individuals and women are encouraged.

Awards in response to this announcement will not be made to foreign
institutions.  Domestic applications can include an international
component as a consortium arrangement if it represents a minor
fraction of the total program and its unique contribution to the
program is well justified.

MECHANISM OF SUPPORT

The support mechanism for this RFA program will be the program
project grant (P01) (containing research projects and the requisite
shared infrastructural resources [cores] as subcomponents under the
aegis of the parent grant).  Support for research projects and cores
at institutions other than the parent grant can be requested as a
consortium arrangement.  However, because of the unique features and
needs of this gene therapy program, the general requirements differ
from those of the traditional program project grant. Special
guidelines have been developed and these instructions must be
followed in responding to this RFA. The total project period for
applications submitted in response to this RFA may not exceed five
years.  The anticipated award date is September 30, 1993.
Administrative adjustments in project period and/or amount of support
may be required at the time of award.  Because the nature and scope
of the research proposed in response to this RFA may vary, it is
anticipated that the size of an award will vary also.

Although it is expected that the investigators of the gene therapy
grants will plan, direct, and execute their own research program, any
substantive modifications in the program must be mutually agreed upon
by the program director, the grantee institution, and the NHLBI.  The
NHLBI will monitor the progress of each program throughout the five
year period of support.

This RFA is a one-time solicitation .  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and be reviewed according to
customary NIH peer review procedures.

A maximum of $1.33 million in total costs in the 01 year with a
maximum of four percent annual escalation thereafter, can be
requested by the applicant.  Since this RFA program seeks to promote
scientific research, as well as infrastructural support, essential to
promoting and accelerating progress in the gene therapy field, there
should be at least three research projects proposed, of which two
must be part of any ultimate award.  Core funding should not exceed
60 percent of the total cost of the grant. The exact balance of the
number of scientific projects and infrastructural resources needed to
promote gene therapy advances is left to the discretion of the
applicant. Although support for several cores may be requested, each
core must be able to demonstrate significant usage by the component
projects of the parent grant and by other investigators with
independently-funded, NIH peer-reviewed projects.

This RFA program especially encourages innovative, high-risk gene
therapy directions by new or established investigators through
pilot/feasibility studies.

Non-CF related heart, lung, and blood gene therapy pilot/feasibility
projects must be submitted in the aggregate as a pilot/feasibility
core.  Funding for such projects is included in the $1.33 million
total cost cap.  A maximum limit of up to $250,000 of the total costs
allotted to cores per year per grant may be budgeted for this core.
Each non-CF related gene therapy pilot/feasibility project may
request up to $50,000 in total costs per year for a maximum of two
years.  New pilot/feasibility projects may be proposed to replace
those that have terminated.  If awarded, these new pilot/feasibility
projects will be subject to the same dollar/time limits.  The
mechanism for selecting and reviewing initial and subsequent
pilot/feasibility projects during the five year tenure of this
program is detailed in the special guidelines governing this program,
available from the program administrator listed at the end of this
announcement.

FUNDS AVAILABLE

Although approximately $4.0 million in total costs for this program
is included in the financial plans for fiscal year 1993, award of
grants pursuant to this RFA is contingent upon receipt of funds for
this purpose.  It is anticipated that three gene therapy programs
will be awarded under this program.  If collaborative arrangements
through subcontracts with other institutions are planned, Tanya McCoy
of the NHLBI Grants Operations Branch should be consulted regarding
procedures to be followed (telephone (301) 496-4970).

The Cystic Fibrosis Foundation (CFF) has particular interest in
supporting the pilot/feasibility components of the gene therapy
programs related to CF and will provide up to $500,000 per year
(direct costs) per parent grant in additional funds for this purpose
(up to a maximum of five years).  These funds do not count toward the
$1.33 million total cost limit set for these gene therapy
applications. Applicants should not include these costs in their
summary budget pages.  However, the specific budget pages should be
included, as they will be part of the initial review. Individual
pilot/feasibility projects may request up to $50,000 per year (direct
costs) for a maximum of two years. New CF-related pilot/feasibility
projects may be proposed to replace those that have terminated.  If
awarded, these new pilot/feasibility projects will be subject to the
same dollar/time limits.  These CF-related pilot/feasibility projects
should be submitted as a group with the application, but clearly
distinguishable from the other pilot/feasibility projects that are
proposed that are non-CF related.  The same review criteria will be
applied to the evaluation of all the pilot/feasibility projects
received in response to this announcement.  However, once the award
decision is made, these projects will go to the CFF who will be
responsible for their funding and management and the mechanism
governing the selection and review of subsequent pilot/feasibility
projects during the five year tenure of this program.

RESEARCH OBJECTIVES

Background

Gene therapy offers tremendous potential for the prevention,
treatment, and cure of a broad range of both single gene disorders
and multifactorial diseases.  Collectively, single-gene disorders,
such as cystic fibrosis, sickle cell anemia, and hemophilia, have a
large impact on human health. Multifactorial disorders, which are due
to complex interactions between one or more genes and the
environment, are much more prevalent and less well understood than
single-gene disorders.  Their economic and social toll is immense,
because they include diseases responsible for the leading causes of
death in the United States, such as heart disease, hypertension,
chronic obstructive pulmonary diseases, and allied conditions,
including asthma.

In spite of its vast potential, gene therapy is still in its infancy,
facing many difficult technical hurdles before it can achieve
wide-spread clinical application.  Current gene transfer protocols
are complex, cumbersome, labor intensive, and costly.  Expanded and
new research efforts are necessary for the basic tasks involved in
gene therapy, including the selection of appropriate target cells,
methods for inserting the new gene into the target cells, ways to
accomplish gene integration at a specific chromosomal location,
achieving appropriate expression of the inserted gene, regulating
gene expression, and development of appropriate animal models.

The excitement, progress, promise, and barriers to gene therapy are
well illustrated in cystic fibrosis research. Cystic fibrosis is the
most common lethal genetic disease in Caucasians.  The disease is a
single gene defect that is caused by mutations in the gene that
encodes the cystic fibrosis transmembrane conductance regulator
(CFTR), resulting in the aberrant transport of ions (chloride and
sodium) across the cell membrane.

The ultimate goal of current research on CF is the development of
safe, effective therapies, or perhaps, even a cure for CF.  Gene
therapy involves correcting an abnormal gene or replacing it with one
that works properly.  This approach holds the promise of a direct
cure for CF pulmonary disease.  An important scientific achievement
has been the correction of the major ion transport abnormality
associated with CF by the insertion of the normal CFTR gene into
defective CF airway cells maintained in laboratory culture. This
forms the cornerstone for development of gene therapy for the CF lung
disease.

Gene therapeutic approaches require the design of an effective
delivery system capable of transferring the normal gene into a large
number of cells in the airways.  Possible delivery systems being
explored include viruses (such as adenovirus, adeno-associated virus,
retroviruses) which infect cells or membrane lipids or cell growth
factors that get internalized by cells.  The relative advantages and
disadvantages of each are being assessed.

An exciting recent discovery has been the development of an animal
model of CF, using transgenic and gene targeting technologies to
disrupt the normal CFTR-like gene in mice.  The existence of such an
animal model is of tremendous value for investigations into the
molecular basis of disease, and for the development and testing of
new modes of treatment, including gene therapeutic strategies.
Additionally, other transgenic mice have been generated that contain
human CFTR which has been directed to specific airway epithelial cell
types via lung epithelial cell specific regulatory elements (i.e.,
promoter enhancer elements).  As gene therapy in CF may require the
transfer of the CFTR gene to specific sites within the airways, these
studies are important because they establish the usefulness of tissue
specific promoters in targeting specific cells within the lung.  The
development and testing of other animal (non-primate and primate)
models are important for assuring the safety of human gene therapy.

Gene therapy also represents an exciting potential new generation of
treatment approaches for patients with cardiovascular, hematologic,
and other pulmonary diseases.  Progress towards gene therapy of these
diseases requires a fundamental understanding of the gene transfer
approaches, long term gene expression systems, the basic biology of
target cells, the development and testing of appropriate animal
models, and the development of appropriate infrastructure resources,
similar to CF.  Although these diseases may differ in the specifics
of the gene therapy approach, there is commonality in many of the
scientific issues and infrastructural resources fundamental to
promoting gene therapy of these diseases.  As a consequence, the
NHLBI will establish special gene therapy research programs, built
around and focused on CF research, but that will also be of important
benefit to the broader heart, lung, and blood gene therapy research
community.

Other

The overall objective of this initiative is to promote research on
approaches to gene therapy for heart, lung, and blood diseases, with
a special emphasis on CF that will lead to a cure for the pulmonary
manifestations of this disease.  Each applicant has flexibility in
devising a plan to accomplish the objectives of this RFA.  Applicants
must propose, with a central focus on gene therapy of CF, a
multiproject, multidisciplinary intra- and/or inter-institutional
research program, comprised of the requisite infrastructural
resources and core functions needed to conduct the proposed
collaborative work.  The research projects and the requisite shared
infrastructural resources, both potentially arising from an amalgam
of different institutions and resources, must be submitted as
subcomponents under the aegis of a single parent grant.  Proposed
research should represent new directions and opportunities and
demonstrate the development of significant key alliances among
investigators in the diverse areas of scientific expertise required
for the further advancement of CF gene therapy research.

To provide a suitable structure for achieving the overall objectives
of this announcement, grant awards will provide support for the
following elements:

o  Inter- And Intra-Institutional Collaborations

This initiative specifically seeks to develop new alliances and
interactions and promote the development or adoption of advanced
technologies needed to accomplish the challenging problem of gene
therapy for the pulmonary manifestations of CF.  A special feature of
this RFA is to encourage Principal Investigators to pool the
disparate scientific and technical expertise and infrastructural
resources of investigators from several institutions, through the use
of subcontracts to the parent grant, in a multi-institutional
collaborative effort important to advancement of gene therapy for
pulmonary disease in CF.

Currently, numerous laboratories are working independently to address
the various problems relevant to gene therapy for CF.  This program
provides a mechanism for inter- and intra- institutional
collaborations among investigators addressing problems relevant to
gene therapy for CF, as the prime focus.  An investigator may propose
a scientific project(s) on gene therapy approaches for other heart,
lung, and blood diseases if the overall major focus of the program,
as a whole, is on CF.  Since this RFA program seeks to support
scientific research, as well as the infrastructural support, there
should be at least three research projects proposed, of which two
must be part of any ultimate award. A substantial time commitment by
the Principal Investigator of the program, who must be a project
leader of a component project, and project leaders of the component
projects is expected.

o Infrastructural Resources

In order to provide the appropriate infrastructure, funds (up to a
maximum of 60 percent of the total cost of the grant) will be
provided to support core resources as shared facilities.  Examples
are:  vector core; tissue culture core; molecular biology core;
transgenic or other types of animal (such as non-primates and
primates) models core; small clinical core (such as for support of a
joint venture to provide resources for expanding a General Clinical
Research Center (GCRC) funded by the NIH National Center for Research
Resources) to facilitate preclinical studies; morphology-morphometry
core.

The generation of these "shared" infrastructural resources is an
important goal of this program, and forms the structural foundation
for the areas of scientific need. 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 design
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.

Progress in gene therapy of other diseases of the cardiovascular,
hematologic, and pulmonary system could be greatly facilitated by
access to these infrastructural resources.  Consequently, applicants
must include a plan that will ensure the availability of these shared
core function(s) to other investigators who have independent research
grant support.

o Pilot/Feasibility Studies To Foster Entry Of Young And Established
Investigators Into The Field Of Gene Therapy Research And To Promote
Innovative Research By Established Gene Therapy Investigators

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 core resources described
above) and funds to pursue innovative pilot/feasibility studies.
Pilot/feasibility and core support will enable established
investigators who did not previously work in gene therapy and new
investigators with state-of-the-art core technologies to be
competitive in the field.

In addition, established investigators in the gene therapy area may
propose high-risk, uncharted innovative directions.  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
RO1s in the area of gene therapy research of CF, as well as other
heart, lung, and blood diseases.

o Institutional Commitment

Success of this special program will also hinge upon a strong,
institutional commitment to the goals of the program.  Institutions
can demonstrate commitment through allocation of space, funds to
support resources, and positions for staff.

The grant applications submitted in response to this announcement
should clearly define the rationale, background and specific aims of
the proposed studies, and should provide a succinct description of
the methods and procedures to be used.

Some areas of opportunity for research that may lead to improved gene
therapy strategies for CF lung disease are cited below to provide a
perspective of the scope of research that would meet the goals of
this program.

o  Development and testing of appropriate vector (viral and nonviral)
systems that will allow effective delivery of the normal CF gene into
the airway epithelium.

o  Development and testing of model systems (animal and in vitro) for
evaluation of gene therapy strategies, as well as assessing safety
and efficacy and for pathogenetic studies.

o  Basic cell biologic questions relevant to successful gene
therapeutic approaches could include:  identification of the
appropriate population of airway cells to be targeted for gene
therapy, the cell types expressing CFTR, the protein product of the
CF gene, the stem cell and/or proliferative compartment of cells, and
the effect of CFTR overexpression on cellular function.

o  Development of appropriate infrastructural resources.

It is not required that all or any of these topics be included.
Investigators are encouraged to consider other relevant approaches to
promoting and accelerating progress towards gene therapy for CF.  As
the infrastructural resources fundamental to promoting gene therapy
of CF pulmonary disease provide a valuable resource for promoting
gene therapy approaches for other cardiovascular, hematologic, and
pulmonary diseases for which a gene has been cloned, CF investigators
must also include plans detailing how access to these infrastructural
"shared" resources by these other investigators will be accomplished.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI will sponsor periodic
meetings to foster cooperation and exchange of information among
investigators who participate in this program.  In the budget for the
grant application, applicants should request travel funds for a
one-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 such
meetings.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS-398
(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
[i.e., Native Americans (including American Indians or Alaskan
Natives), Asian/Pacific Islanders, Blacks, Hispanics].  The rationale
for studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and prevention strategies), diagnosis, or treatment of
diseases, disorders or conditions, including, but not limited to,
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit by January 25, 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 any application subsequently submitted,
the information that it contains allows Institute 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:

Chief, Centers and Special Projects Review Section
Review Branch, Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553
Bethesda, MD  20892
Telephone:  (301) 496-7351
FAX:  (301) 496-7033

APPLICATION PROCEDURES

Submit applications on form PHS 398 (rev. 9/91), the application form
for research project grants.  This form is available in an applicant
institution's office of sponsored research; from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone
301/496-7441; and from the NIH program administrator named below.

However, because form PHS-398 is used primarily for the traditional
individual research grant application, 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 the NHLBI Program
Administrator.

The RFA label included in form PHS 398 (rev. 9/91) must be affixed to
the bottom of the face page of the original completed 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, including
the Checklist, and three signed, photocopies in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to the Chief, Centers and Special Projects Section
at the address listed under LETTER OF INTENT.  It is important to
send these two copies at the same time as the original and three
copies are sent to the Division of Research Grants.  Otherwise, the
NHLBI cannot guarantee that the application will be reviewed in
competition for this RFA.

Applications must be received by April 22, 1993.  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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
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 the NHLBI peer review group on the
basis of relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be noncompetitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications judged to be competitive
will undergo further scientific merit review, including, if deemed
appropriate, a reverse site visit at the applicant's expense or a
site visit.  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.

Applicants should submit the highest quality application possible to
the DRG.  Revisions of applications (addition and deletion of
project, cores, or studies) after submission will not be permitted.
The grant applications may not be modified by the applicant during
the review process, which begins with the submission of the
application to DRG.  All projects reviewed at a reverse site visit or
site visit will be included when it is considered at the second level
of review by the National Heart, Lung, and Blood Advisory Council.

During the review, individual projects will be "not recommended for
further consideration" by the reviewers only if they are considered
not to have "significant or substantial" scientific merit and will be
deleted only if they do not fit into the overall programmatic theme
of the application.

The major factors to be considered in the evaluation of applications
will be:

1.  Scientific and technical merit of each proposed project,
including the novelty, originality, feasibility, and the adequacy of
the experimental design.

2.  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.

3.  Adequacy of the resources and facilities to support the proposed
clinical and basic research.

4.  Plans for access of "shared" core facilities to investigators
exploring gene therapy for other cardiovascular, hematologic, or
pulmonary disease targets for which the gene has been cloned,
including those undertaking pilot/feasibility studies.

5.  Integration of the various components into an effective gene
therapy program, emphasizing CF, and the adequacy of plans for
interaction and dissemination of information among the intra- and
inter-institutional collaborators.

6.  Competence of the investigators to accomplish the proposed
research goals, and the adequacy of their time commitments for the
work proposed.

7.  Qualifications, experience, and commitment of the program
director and the director's ability to devote adequate time and
effort to provide scientific and administrative leadership to the
gene therapy program.

8.  Willingness to interact with other CF gene therapy programs and
with the NHLBI.

9.  Adequacy of internal and external procedures for monitoring and
evaluating the proposed research and for providing on-going quality
control and scientific review.

10.   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 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 Administrator.

Other factors that will be considered in the evaluation of
applications include:

1.  Commitment of the grantee institution and any cooperating
institutions to the program, and the appropriateness of its resources
and policies for the administration of a research program of the type
proposed; and

2.  Appropriateness of the requested budget to the work proposed.

AWARD CRITERIA

The anticipated date of award is September 30, 1993.

The following criteria will be considered in making funding
decisions:

o  Scientific and technical merit, reflected in the priority score
o  Scope of the applications received
o  Availability of funds
o  Relevance to NHLBI program objectives

Timetable

Letter of Intent                    January 25, 1993
Application Receipt Date            April 22, 1993
Review by National Heart, Lung,
 and Blood Advisory Council         September 2-3, 1993
Anticipated Award Date              September 30, 1993

INQUIRIES

Inquiries regarding programmatic issues related to this announcement
may be directed to:

Susan P. Banks-Schlegel, Ph.D.
Airways Diseases Branch
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 6A15
Bethesda, MD  20892
Telephone:  (301) 496-7332

Inquiries regarding fiscal matters may be directed to:

Tanya McCoy
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A17A
Bethesda, MD  20892
Telephone:  (301) 496-4970

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.838.  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 to review by a Health
Systems Agency.

.

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