Full Text DK-93-05


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

RFA:  DK-93-05

P.T. 04

  Pulmonary Diseases 
  Gene Therapy+ 
  Disease Prevention+ 
  Treatment, Medical+ 
  Biomedical Research, Multidiscipl 

National Institute of Diabetes and Digestive and Kidney Diseases
Cystic Fibrosis Foundation

Letter of Intent Receipt Date:  February 22, 1993
Application Receipt Date:  April 22, 1993


The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the Cystic Fibrosis Foundation (CFF) invite applications
for Core Center Grants (P30) to enhance research leading to
successful gene therapy of cystic fibrosis and other genetic diseases
of interest to the NIDDK.  Core Centers will provide shared resources
to facilitate multidisciplinary collaborative approaches to achieving
the treatment, prevention and cure of cystic fibrosis and other
genetic diseases through gene therapy.  Biomedical research cores are
intended to enhance the efficiency of research and foster
collaborations within and among institutions with strong existing
bases of research relevant to gene therapy.  In addition to
biomedical research cores, Centers provide support for innovative
pilot and feasibility studies and an enhanced environment for
research training.

This program is intended to further the exciting recent progress
toward gene therapy of cystic fibrosis, and applicants should propose
a central focus on gene therapy of cystic fibrosis.  However, issues
in developing safe methods for targeting and inserting genes and
achieving gene integration and expression are common to a variety of
genetic diseases and accomplishments have general relevance to
advancing gene therapy for cystic fibrosis and other diseases of
interest to the NIDDK.  Therefore the shared biomedical research
cores are also available to scientists developing gene therapy
approaches to genetic endocrine, metabolic, digestive, liver, kidney,
urologic 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 RFA,
Core Centers for Gene Therapy of Cystic Fibrosis and Other Genetic
Diseases, is related to the priority area of chronic diseases.
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).


Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Minority individuals
and women are encouraged to submit as Principal Investigators.
Foreign institutions are not eligible to apply.


Support of this program will be through the NIH grant-in- aid core
center (P30) award.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the
applicant.  Except as otherwise stated in this announcement, awards
will be administered under PHS grants policy as stated in the PHS
Grants Policy Statement.


The NIDDK expects to award two new P30 Core Center Grants in fiscal
year 1993 on a competitive basis.  The anticipated award will be for
five years and is contingent upon the availability of appropriated
funds.  The NIDDK anticipates that approximately $2.0 million may be
available for total costs of these awards in FY 1993.  The annual
direct costs requested may not exceed $750,000, with two exceptions.
One exception to the $750,000 cap will apply to Core Center
applications that include subcontracts.  In such cases, the indirect
costs related to the subcontracts will be excluded from the requested
direct cost levels prior to the application of the cap.  The CFF has
a particular interest in supporting pilot/feasibility studies
directed at developing gene therapy for cystic fibrosis, and funding
for this component of the center may be provided by the CFF.
Therefore these costs are not included in the $750,000 limit on
direct costs.  Pilot and feasibility studies on cystic fibrosis
should be included as part of the application and will be reviewed as
a component of the Center, but funded through a separate award from
the CFF.  The CFF will award up to $500,000 per year direct costs for
a maximum of five years to each center for such pilot/feasibility
studies  Pilot and feasibility studies on other genetic diseases are
included in the $750,000 cap.  Up to five years duration of support
for the pilot and feasibility program as a whole may be provided.
However, each individual pilot/feasibility study is limited to
$50,000 per year and a two year duration of support.



Cystic fibrosis (CF) is the most common fatal genetic disease in
caucasians, affecting approximately one in 2500 newborns.  The
identification and cloning of the CF gene, together with development
of techniques that permit routine introduction of functional genes
into mammalian cells and proper expression of these genes, present
the opportunity to direct gene therapy at the basic defect underlying
cystic fibrosis.  Introduction and expression of the normal CF gene
has already been achieved in cells from patients with cystic fibrosis
with successful correction of the defect in chloride transport.
Strategies for effective gene therapy of cystic fibrosis in vivo are
now being developed and tested.  A variety of delivery vehicles with
affinity for pulmonary epithelial cells are under active
investigation.  In addition cell specific promoters are being
utilized to target gene expression specifically to pulmonary
epithelial cells.  For example, transgenic mice have been created in
which CFTR expression is controlled by the SP-C gene promoter; these
mice produce CFTR in pulmonary epithelium with no apparent pulmonary
dysfunction or morphologic alteration.  Further, low levels of CFTR
expression have been achieved in cotton rats using a replication
defective adenovirus construct.  Other recent data suggests that
genetic correction of only a fraction of airway cells in vitro is
required to restore normal epithelial cell function.  These
encouraging results support the feasibility of gene therapy for this
disorder.  However, the precise sites and cell types in which
expression of CFTR will correct the clinical disorder and the optimal
method for achieving such expression remains to be determined, and
safety issues must be addressed.  Core Centers will provide resources
needed for further research to bring gene therapy to fruition as a
treatment for cystic fibrosis.

Although many other individual genetic metabolic diseases are quite
rare, in the aggregate they are responsible for a substantial burden
of disease.  Gene therapy for one such disorder, adenosine deaminase
(ADA) deficiency, is already a reality with ex vivo correction of ADA
deficient cells and return of these cells to children.  Advances in
cellular and molecular biology have resulted in elucidation of the
molecular mechanisms responsible for many genetic diseases.  An
essential first step toward gene therapy is being achieved as the
genes responsible are identified and cloned in an increasing number
of these disorders.  Although some issues such as the target cell
types for correction are unique for each disorder, progress toward
gene therapy of cystic fibrosis and other genetic diseases now
depends on developing and testing technology relevant to a number of
these disorders.  Such methods can most efficiently be developed if
shared resources are available to support individual research

The NIDDK-supported Cystic Fibrosis Research Centers are part of an
integrated program of cystic fibrosis-related research support.
These centers have provided a focus for increasing collaboration and
cost effectiveness among groups of successful investigators at
institutions with established comprehensive cystic fibrosis research
bases. The NIDDK supports four Specialized Centers of Research (P50)
and one Core Center Grant (P30) in Cystic Fibrosis.  In addition, the
NIDDK supports a large body of research on cystic fibrosis and other
genetic diseases and gene therapy for these disorders through regular
research and program project grants.  Core Center Grants on Gene
Therapy of Cystic Fibrosis and Other Genetic Diseases are intended to
improve the quality and efficiency of research on gene therapy of
these disorders by providing shared access to specialized technical
resources and expertise.

Objectives and Scope

The objectives of the Core Centers for Gene Therapy of Cystic
Fibrosis and Other Genetic Diseases are to bring together
investigators from relevant disciplines in a manner which will
enhance and extend the effectiveness of their research.  These Core
Centers may serve as national resources.  In addition to
collaborations between scientists within an institution, core centers
can foster interaction and collaborations between investigators at
multiple institutions to promote a multifaceted approach to a common
goal.  While utilization of core resources by research programs
outside the primary institution where the center is based is
encouraged,  a core center must be an identifiable unit within a
single university medical center or a consortium of cooperative
institutions, including an affiliated university.  An outstanding
existing program of biomedical research in the area of gene therapy
of cystic fibrosis and other genetic disorders is required.  This
research should be in the form of NIH-funded research projects,
program projects, or other peer-reviewed research such as that
supported by the Cystic Fibrosis Foundation.  This established
research program must be in existence at the time of submission of a
center application.  The initial base of research projects to be
served by the cores must be clearly defined in the application.  The
process by which additional projects will be selected to utilize the
core resources and by which selected projects will be prioritized
must be delineated.  Efficient management of resources and close
cooperation, communication, and collaboration among involved
personnel in multiple professional disciplines are ultimate
objectives of core centers.

Cores are defined as shared resources that enhance productivity or in
other ways benefit a group of investigators working on gene therapy
of cystic fibrosis and other genetic diseases of interest to the
NIDDK to accomplish the stated goals of the center.  Examples of
possible core resources that would be considered responsive to this
request for applications include the following:

o  vector core to develop innovative approaches to vector design, to
assist investigators with construction of vectors, to provide large
scale production of vectors meeting the Food and Drug Administration
requirements for vectors intended for human use, and to monitor and
assess vector quality and safety;

o  molecular biology core to supply oligonucleotides and provide
automated DNA sequencing capability;

o  animal models core to develop, breed and maintain animal models
for cystic fibrosis and other genetic metabolic diseases which can be
used in in vivo assessment of gene therapy protocols;

o  cell morphology core to assess efficiency of gene transfer using
techniques such as enzymatic histochemistry, immunohistochemistry or
in situ hybridization and to characterize transfected tissues
morphologically at the level of light or electron microscopy;

o  tissue culture core for the harvest, cultivation, infection and
handling of large numbers of cells;

o  surgery/delivery core to develop techniques for implantation of
transfected cells or for direct introduction of vectors to target
tissues or organs;

o  human applications core to assist with generation of preclinical
data in a dedicated facility using good laboratory practice/good
manufacturing practice to ensure that the data generated will be
satisfactory for application for Investigational New Drug permits;

o  other cores needed to characterize gene transfer systems in terms
of specificity and organ distribution of uptake, and level and
duration of transgene expression, and to identify transcriptional
elements that confer high level transgene expression in particular

These possible cores are not listed in any particular order nor do
they represent a comprehensive list of cores that could be fostered
under this request for applications.  Applicants are encouraged to
propose other cores that address the program objectives stated above.

Two other types of activities may also be supported with center
funding:  a pilot and feasibility program and an enrichment program.
The pilot and feasibility program provides modest support for
innovative new initiatives with the potential to significantly
advance progress toward gene therapy.  This program is directed at
new or established investigators who wish to explore the feasibility
of a novel approach to a problem in this area.  The center grant may
also include limited funds for program enrichment such as seminars,
visiting scientists, consultants, and workshops.

Investigators eligible for pilot and feasibility funding generally
fall into three categories:  (1) new investigators without current or
past NIH research project support (R01, R29, P01) as a Principal
Investigator (current or past support from other sources should have
been modest); (2) established investigators with no previous work in
gene therapy of cystic fibrosis or other genetic metabolic diseases
who wish to apply their expertise to a problem in this area; and (3)
established investigators in these areas who propose testing
innovative ideas that represent clear departure from ongoing research
interests.  It is expected that the majority of the investigators
will fall into the first category.  All eligible investigators,
however, must have faculty appointments and be independent
investigators.  Postdoctoral fellows or their equivalent are not
eligible.  Each pilot and feasibility study proposal should state
clearly the justification for eligibility of the investigator under
one of the above three criteria.

In addition each pilot and feasibility proposed should state clearly
whether it address cystic fibrosis or another genetic disease.
Projects addressing cystic fibrosis are not included in the $750,000
limit on direct costs since they may be funded through a separate
award from the CFF.  Such projects should be clearly grouped and
distinguished from pilot projects on other genetic diseases that are
included in the $750,000 limit on direct costs requested.  A proposed
pilot and feasibility study should present a testable hypothesis and
clearly delineate the question being asked, detail the procedures to
be followed, and discuss how the data will be analyzed.  It must be
on a topic related to the objectives of the Core Center.  It should
be submitted generally using the NIH research project application
(R01) format.  However the applications should be abbreviated with
the description of the project limited to five pages.  Projects
should be focused, since funding for individual studies is modest and
is limited to two years or less.  Any one investigator is eligible
only once for this support, unless the additional proposed pilot and
feasibility study constitutes a real departure from his/her ongoing

A pilot and feasibility study award is intended to provide modest
support which will allow an investigator the opportunity to develop
sufficient preliminary data to provide the basis for an application
for independent research support.  Pilot and feasibility study
support is not intended for large projects by established
investigators which would otherwise be submitted as separate research
grant applications.  Pilot and feasibility funds are also not
intended to support or supplement ongoing funded research of an

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  In such a case, a letter of agreement from
either the GCRC program director or principal investigator could be
included with the application.


It is NIH policy that women and minorities must be included in
clinical study populations unless there is a good reason to exclude
them.  The study design must seek to identify any pertinent gender or
minority population differences.


NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are 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 must 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 must be provided. This policy is applicable for every
individual study or project proposed in the application.

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 must 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. 09/91) in Item 4 (Research Design and Methods) of the Research
Plan AND summarized in Item 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 is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention [and preventive 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 without review.


Potential applicants are strongly encouraged to submit a letter of
intent no later than February 22, 1993.  The letter of intent need
only include (1) names of the Principal Investigator/program director
and principal collaborators, (2) descriptive title of the potential
application, (3) identification of the organization(s) involved, and
(4) reference to the RFA number "DK-92-05."

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramual Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephoen:  (301) 496-7083

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 the review of applications.
It allows NIDDK staff to estimate the potential review workload and
to avoid conflict of interest in the review.


Applicants should request a copy of "Guidelines for Core Centers for
Gene Therapy of Cystic Fibrosis and Other Genetic Diseases."  These
guidelines contain important additional information on the format,
content, and review of applications and review criteria.  Prospective
applicants may obtain guidelines from Dr. Judith E. Fradkin at the
address listed under INQUIRIES.

Applications are to be submitted on the form PHS 398 (rev. 09/91)
available at most institutional offices of sponsored research and
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.  On item 2a of the face
page of the application, applicants must enter: "RFA:  Gene Therapy
Centers, RFA number DK-93-05."  The RFA label available in the
application form PHS 398 must be affixed to the bottom of the face
page.  Failure to use this label could result in delayed processing
of the application to the extent that it may not reach the review
committee in time for review.

Applications must be received by April 22, 1993.  The original and
three copies of the application must be sent or delivered to:

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

Two additional copies of the application under separate cover must be
sent to:

Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892


Upon receipt, applications will be initially reviewed by the Division
of Research Grants (DRG) for completeness.  Incomplete applications
will be returned to the applicant without further consideration.
Evaluation of responsiveness to the program requirements and criteria
stated in this RFA is an NIDDK staff function.

Those applications that are complete and responsive will be evaluated
in national competition in accordance with the criteria stated below
and in the Core Center Guidelines for Scientific/technical merit by
an appropriate peer review group convened by the NIDDK.  Applications
may be subjected to triage by an NIDDK peer review group to determine
their scientific merit relative to other applications received in
response to this RFA.  If the number of applications is large
compared to the number of awards to be made, a preliminary scientific
peer review may be conducted and applications withdrawn from further
competition when they are not competitive for the award.  The NIDDK
will notify the applicant and institutional official of this action.
It is essential that the written application be in a form to be
reviewed on its own merit, since no site-visit is anticipated.
Following this review, the applications will be given a second level
review by the National Diabetes and Digestive and Kidney Diseases
Advisory Council.

The initial review group will review each application using the
criteria stated below:

o  Scientific excellence of the Center's research base that should
have a broad and central focus in gene therapy of cystic fibrosis and
may extend to gene therapy of other genetic diseases relevant to the
mission of the NIDDK.  The relevance of the separately funded
research to the Core Center and the likelihood for meaningful
collaboration among Center investigators must be demonstrated.

o  Appropriateness and relevance of the cores and their modes of
operation, facilities, and potential for contribution to ongoing

o  The pilot and feasibility program is judged on the basis of (1)
scientific merit of the studies as submitted and (2) the merit of the
administrative process for selecting subsequent studies.

o  Efficiency and effectiveness of use and/or planned use of
enrichment funds.

o  The scientific and administrative leadership abilities of the Core
Center Director and Associate Director and their commitment and
ability to devote adequate time to the effective management of the
Core Center.

o  The appropriateness of the Core Center budgets for the proposed
and approved work to be done in core facilities, for pilot and
feasibility studies, and for enrichment in relation to the total
Center program.

o  Institutional commitment to the program, including lines of
accountability regarding management of the Core Center grant and a
commitment to establish new positions as necessary.

o  Enriched academic environment with resources to enable the
activities to be conducted.

o  Appropriateness, suitability and integration of research training
and other training programs into the overall Center.


Applications will compete for available funds with all other
applications submitted in response to this RFA and recommended by
peer review.  The following will be considered in making funding

o  Quality of the proposed center as determined by peer review
o  Availability of funds
o  Overall balance in the Core Center program


Letter of Intent:     February 22, 1993
Application Receipt:  April 22, 1993
Initial Review:       June-July 1993
Second Level Review:  September 1993
Anticipated Award:    September 30, 1993


Written and telephone inquiries concerning this RFA are encouraged.

Direct inquiries regarding programmatic issues to:

Judith E. Fradkin, M.D.
Chief Endocrinology and Metabolic Diseases Research Branch and
 Cystic Fibrosis Program Director
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 621
Bethesda, MD  20892
Telephone:  (301) 496-7991

Direct inquiries regarding fiscal matters to:

Sharon F. Tempchin
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 639
Bethesda, MD  20892
Telephone:  (301) 496-7467


This program is described in the Catalog of Federal Domestic
Assistance No. 93.847.  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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