Full Text DK-97-010
NIH GUIDE, Volume 26, Number 12, April 11, 1997
RFA:  DK-97-010
P.T. 04

  Gene Therapy+ 
  Metabolic Diseases 
  Digestive Diseases & Disorders 

National Institute of Diabetes and Digestive and Kidney Diseases
Cystic Fibrosis Foundation
Letter of Intent Receipt Date:  January 12, 1998
Application Receipt Date:  February 10, 1998
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK)and the Cystic Fibrosis Foundation invite applications for
Core Center Grants to support gene therapy research on cystic
fibrosis and other genetic diseases of interest to NIDDK.  Core
Centers will provide shared resources to enhance the efficiency of
research and foster collaborations within and among institutions with
strong existing bases of research relevant to gene therapy.  Centers
will also support a Pilot and Feasibility Program and an Educational
Enrichment Program.
This program is intended to foster research toward the goal of gene
therapy for cystic fibrosis.  Therefore, applicants should propose a
central focus on gene therapy for cystic fibrosis.  However, many
common principles are involved in the development of safe methods for
targeting and achieving long-term expression of therapeutic genes for
most genetic disease.  Therefore, Core Center resources may also be
made available to scientists developing gene therapy approaches for
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,
Gene Therapy Core Centers, 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 Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone:
Applications may be submitted by domestic for-profit and nonprofit
organizations, public or private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal Government.  Foreign institutions
are not eligible to apply.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as
Principal Investigators.
This RFA is a one-time solicitation.  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 Public Health
Service (PHS) grants policy as stated in the PHS Grants Policy
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.  If so, a letter of agreement from either the
GCRC program director or principal investigator should be included
with the application.
The NIDDK expects to award three P30 Core Centers on a competitive
basis, two in late FY 1998 and one in early FY 1999.  The receipt of
three competing continuation applications is anticipated.  These will
compete together with new applications received in response to this
announcement.  NIDDK anticipates that approximately $2.8 million will
be available for the total cost of these awards; however, this
funding level is dependent upon the receipt of a sufficient number of
applications of high scientific merit.  Although this program is
provided for in the financial plans of the NIDDK, the award of grants
pursuant to this RFA is also contingent upon the availability of
funds for this purpose.
In a separate award, the Cystic Fibrosis Foundation (CFF) will award
up to $500,000 per year direct costs for a maximum of five years to
each center for pilot and feasibility studies to develop gene therapy
for cystic fibrosis.  All pilot and feasibility projects will be
reviewed as a single component of the Gene Therapy Core Center.  To
be eligible for CFF funding, applicants will need to provide the CFF
with a copy of the review.
The total project period for applications submitted in response to
this RFA is five years.  The maximum dollar request for the NIDDK
award is limited to $750,000 in direct costs in any budget period.
Pilot and feasibility studies proposed for funding by NIDDK are
included in the $750,000 limit.  An additional budget of up to
$500,000 for pilot and feasibility projects on cystic fibrosis is
excluded from the $750,000 limit.  Any indirect costs related to
subcontracts are not included in the $750,000 direct cost limit.
Budget escalations in future years should be limited to 3% up to the
$750,000 limit.  The earliest anticipated award date is 09/30/98.
Genetic diseases, although individually rare, in aggregate account
for a considerable health care burden. For many genetic diseases, the
genes have been cloned and characterized so that gene therapy could
be a possible treatment especially for diseases where current therapy
is inadequate.  Over the past several years, gene therapy clinical
trials have been undertaken in an attempt to develop treatments for
several genetic diseases.  Cystic fibrosis, one of the most common
life-limiting genetic diseases affecting 30,000 Americans, has been
at the forefront of testing this new technology to treat clinical
disease.  In 1989, the gene responsible for CF was cloned and was
designated, the cystic fibrosis transmembrane conductance regulator
(CFTR). Subsequently, CFTR was shown to function as a cAMP- regulated
chloride channel whose disruption results in the CF phenotype.  This
discovery paved the way for the initiation of over 10 gene therapy
clinical trials to express the normal CFTR gene.  These have included
a variety of viral and non-viral strategies using adenoviral vectors,
adeno-associated viral vectors and cationic liposomes to deliver
CFTR.  The first completed studies using adenoviral vectors and
liposomes have identified many limitations of the current technology
for gene therapy including low transfection efficiency, immunological
reactions to the viral proteins, and short duration of gene
expression, as well as the need to identify reproducible surrogate
clinical end-points.
Clinical studies in other genetic diseases have also identified
similar limitations for gene therapy.  For some diseases, where the
defective gene does not produce a protein product (so called null
mutations), expression of the therapeutic gene can elicit an immune
response which extinguishes expression.  In addition, identification
and targeting of stem cells for many tissues have been a significant
road block to long-lasting correction.  Although some issues, such as
targeting the appropriate cell type, are unique for each disorder,
progress toward gene therapy of cystic fibrosis and other genetic
diseases depends on developing and testing technology relevant to a
number of disorders. These problems cut across many different
scientific disciplines and will require collaborative efforts to
develop novel solutions.  Such methods can most efficiently be
developed if shared resources are available to support individual
research projects.
The NIDDK-supported Gene Therapy Core Centers are part of an
integrated program of cystic fibrosis and metabolic disease research.
These Core Centers provide increased, cost-effective collaboration
among multidisciplinary groups of investigators at institutions with
an established, comprehensive research base in cystic fibrosis and
other genetic diseases.  Additionally, NIDDK supports four
Specialized Centers of Research (P50) and one Core Center Grant on
cystic fibrosis.  NIDDK supports a large body of research on cystic
fibrosis and genetic metabolic diseases and gene therapy for these
disorders through regular research and program project grants. Gene
Therapy Core Center grants for cystic fibrosis and other genetic
diseases are intended to improve the quality and multidisciplinary
nature of research on gene therapy of these disorders by providing
shared access to specialized technical resources and expertise.
Objectives and Scope
The objective of the Gene Therapy Core Centers is to provide shared
resources to investigators with a wide variety of relevant expertise
to promote a multifaceted approach to gene therapy research.  Gene
therapy research involves many specialized technologies which need to
be integrated into a cohesive research program.  A Gene Therapy Core
Center would make these technologies available to many investigators
to apply to their research.
A biomedical research core is defined as a shared resource that
provides essential services, techniques, or instrumentation to Center
participants enabling them to conduct their funded individual
research projects more efficiently and/or more effectively.  Cores
provide specialized technologies and expertise needed to accomplish
the stated goals of the Center toward gene therapy of cystic fibrosis
and other genetic diseases of interest to NIDDK.  Each core should
provide services to multiple funded research projects.  Examples of
possible biomedical core resources that would be considered
responsive to this Request for Applications include:
o  Vector core to develop new vector designs, assist investigators
with the construction of vectors, provide vectors for
experimentation, and monitor vector preparations and patient samples
for adventitious agents and replication competent viruses.
o  DNA Delivery core to develop, distribute and test new formulations
for liposome or other DNA compacting and targeting reagents for
delivery of DNA.
o  Animal Models core to develop, breed and maintain models for
cystic fibrosis, to develop new models using knockout technology for
other genetic metabolic diseases, and crossbreed mice on to new
background strains to attain appropriate models for in vivo
assessment of gene therapy.
o  Histology core to assess the efficiency of gene transfer to
particular cell types by using enzymatic histochemistry,
immunohistochemistry, in situ hybridization or in situ polymerase
chain reaction (PCR).
o  Cell Transduction core to develop techniques for transfection of
cells ex vivo and techniques for reimplantation of transduced cells.
o  Electrophysiology core to measure the functional correction of
CFTR in cystic fibrosis cell lines and patient samples.
o  Immunology core to analyze in vivo immunological responses to
transgene and viral proteins and study methods to suppress these
o  Clinical core to design, carry out, and provide statistical
support for gene therapy clinical trials for cystic fibrosis and
other genetic diseases.
o  GMP core facility to produce DNA or vectors for human use under
Good Manufacturing Practice and to generate data for an
Investigational New Drug application.
These possible cores are not listed in any particular order nor do
they represent a comprehensive list of cores that could be supported
under this Request for Applications.  Applicants are encouraged to
propose other cores that address the program objectives as stated
In addition to biomedical cores, an administrative core must be
described which will be responsible for allocation of resources
within the Center and distribution of resources to Center
participants.  The Administrative core will also be responsible for
planning the Educational Enrichment Program consisting of a seminar
series, guest lectures, and workshops, and convening a Committee to
oversee the solicitation, review and selection of the pilot projects.
Although funds are not provided directly for training purposes, the
core laboratories and program enrichment activities should provide
training opportunities for Center members.
Each Core Center must develop a cohesive pilot and feasibility
program to develop new research directions or provide an opportunity
for new investigators or established investigators to enter the field
of gene therapy.  A pilot and feasibility project is intended to
provide modest support which will allow an investigator the
opportunity to develop sufficient preliminary data as a basis for an
application for independent research support.  Pilot and feasibility
projects are not intended to support or supplement ongoing research
of an established investigator.  This Program should be integrated
into the overall research goals of the Center and make use of the
resources provided by the cores. Each Core Center application must
include a minimum of two pilot studies in its requested NIDDK
support.  In addition, the CFF will support up to 10 pilot projects
relevant to gene therapy of cystic fibrosis.  Each pilot project may
request a maximum of $50,000 for up to two years.
An existing program of excellence in biomedical research in the area
of gene therapy for cystic fibrosis and related genetic metabolic
diseases is required.  This research base must consist of NIH and
other peer-reviewed funded research projects and be substantial to
justify the requested Core support.  Suggestions for describing and
presenting this research base in the application are included in the
Administrative Guidelines (See Application Procedures).
It is the policy of the NIH that women and members of minority groups
and their sub-populations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification are
provided that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research.  This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
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 in the NIH
Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.
Prospective applicants are asked to submit, by January 12, 1998, 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 NIDDK staff to estimate the
potential review workload and avoid conflict of interest in the
The letter of intent is to be sent to:
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505
Applicants should request a copy of "Administrative Guidelines for
Gene Therapy Core Centers."  These guidelines contain important
additional information on the format, content, and review of
applications and review criteria.  Prospective applicants may obtain
guidelines from Dr. Catherine McKeon at the address listed under
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 Division of Extramural Outreach and Information Resources,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/435-0714, email:
The RFA label available in the PHS 398 (rev. 5/95) 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 2 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, plus 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 time of submission, two additional copies of the application must
be sent to:
Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F - MSC 6600
BETHESDA, MD  20892-6600
Applications must be received by February 10, 1998.  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.  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 previously reviewed, but such applications
must include an introduction addressing the previous critique.
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 process in which only those
applications deemed to have the highest scientific merit will be
discussed, assigned a priority score, and receive a second level
review by the National Diabetes and Digestive and Kidney Diseases
Advisory Council.
Review Criteria
o  Scientific excellence of the Center's research base which should
have a central focus in gene therapy of cystic fibrosis and may
extend to gene therapy of other genetic diseases relevant to the
mission of NIDDK.  The integration of the research base into the
goals of the Center and collaboration between Center investigators
must be described;
o  The scientific and administrative abilities of the Center Director
and Associate Director and their commitment and ability to devote
adequate time to the effective management of the Core Center;
o Appropriateness, impact, relevance and uniqueness of the services
provided by the cores.  Renewal applications must demonstrate core
usage, cost effectiveness and research progress;
o  For new applications, the pilot and feasibility program is judged
on the basis of (1) scientific merit of the submitted projects and
(2) the merit of the administrative process for selecting subsequent
studies. In competitive renewal applications, emphasis is placed on
the program as a whole, including past research accomplishments,
success in attaining research support and management of the program;
o  The appropriateness of the Core Center budgets for the core
facilities, pilot and feasibility studies, and for enrichment and the
proportion of funds devoted to each component 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; and
o  Adequacy of plans to include patients of both genders and
minorities and their subgroups as appropriate for the scientific
goals of the research.  Plans for the recruitment and retention of
subjects will also be evaluated.
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
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 Gene Therapy Core Center program.
Letter of Intent Receipt Date:  January 12, 1998
Application Receipt Date:       February 10, 1998
Initial Review:                 June-July 1998
Second Level Review:            September 17-18, 1998
Anticipated Date of Award:      Sept 30, 1998 through January 1, 1999
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Catherine McKeon, Ph.D.
Metabolic Diseases and Gene Therapy Research Program
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8810
FAX:  (301) 480-3503
Email:  McKeonC@ep.niddk.nih.gov
Direct inquiries regarding fiscal and administrative matters to:
Donna Huggins
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8848
Email:  HugginsD@ep.niddk.nih.gov
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
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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