Full Text AI-95-011


NIH GUIDE, Volume 24, Number 10, March 17, 1995

RFA:  AI-95-011

P.T. 34

  Biology, Molecular 
  Gene Therapy+ 
  Immune System Disorders 

National Institute of Allergy and Infectious Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases

Letter of Intent Receipt Date:  July 15, 1995
Application Receipt Date:  November 15, 1995


The National Institute of Allergy and Infectious Diseases (NIAID) and
the National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS) of the National Institutes of Health (NIH) invite
submission of investigator-initiated research applications for basic
and preclinical studies targeted at molecular methods for
transferring genes into cells of mucosal membranes and synovial
tissues to augment host defenses and alter inflammatory responses for
the treatment or prevention of infectious and rheumatic and other
immunologic 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), Mucosal and Synovial Gene Transfer in
Infection/Inflammation, is related to the priority areas of diabetes
and chronic disabling diseases and immunization and infectious
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
(202) 782-3238).


Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private institutions, 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 for First Independent
Research Support and Transition (FIRST) (R29) awards.  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.


The mechanisms of support will be the individual research project
grant (R01) and the FIRST (R29) award.  The total project period for
an application submitted in response to this RFA may not exceed five
years; a foreign application may not request more than three years of
support.  Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant.

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

The National Heart, Lung, and Blood Institute (NHLBI) also has
interest in supporting applications concerned with gene transfer to
respiratory cells for the purpose of modulating host defense
processes and inflammatory responses which may apply to treatment or
prevention of infectious or inflammatory diseases.  For applications
of mutual interest, the NHLBI is likely to be given a secondary
assignment in accordance with DRG Referral Guidelines.


The estimated funds available for the total (direct and indirect)
first-year costs of all awards made under this RFA will be $950,000,
$750,000 from the NIAID and $200,000 from the NIAMS.  In Fiscal Year
1996, the NIAID plans to fund approximately three to four R01s and/or
R29s and the NIAMS plans to fund one R01/R29.  The NIH is currently
limiting annual inflationary increases to no more than four percent
for future years of awards.  The usual PHS policies governing grants
administration and management will apply.  This level of support is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  Although this program is provided for in the
financial plans of the NIAID and the NIAMS, awards pursuant to this
RFA are contingent upon the availability of funds for this purpose.
Funding beyond the first and subsequent years of the grant will be
contingent upon satisfactory progress during the preceding years and
availability of funds.



The pathogenesis of many infectious diseases involves a combination
of mucosal colonization, production and release of toxins and
invasion of tissue.  Both host and microbial factors that may
contribute to or limit infection are now being understood at
molecular and genetic levels.  Among these are microbial adhesins and
virulence factors important for attachment and penetration of host
tissues; opsonic factors and host cell surface molecules involved in
microbial adherence and uptake; antimicrobial peptides of phagocytic
and mucosal cells; host cellular factors that may alter microbial
metabolism as well as microbial toxins that may mediate inflammation
through effects on host cell metabolism.

Gene transfer into mucosal cells offers the potential to modify the
course of infectious diseases by altering the expression of factors
that participate in host/pathogen interactions.  Potential advantages
might include an ability to change colonization and tissue invasion
in clinical situations where effective antibiotics are lacking;
providing antimicrobials in high concentrations at critical sites;
and altering cell turnover in targeted tissues (increased

The ability to transfer into mucosal cells genes that encode
molecules that are anti-microbial, anti-inflammatory, or vaccine
epitopes would confer enormous advantages in treating or preventing
infectious and immunologic diseases.  Mucosal gene transfer could be
a useful adjunct in a variety of clinical situations including:  (a)
viral, bacterial, fungal or parasitic infections of the respiratory
and gastrointestinal tracts; (b) infection of the genitourinary tract
and sexually transmitted diseases (STDs); (c) intrabdominal and post
surgical wounds as well as decubitus ulcers; (d) mucosal vaccination
with recombinant immunogens; (e) noninfectious inflammatory disorders
involving mucosal tissues such as asthma; and (f) introduction of
self molecules into the gastrointestinal tract for induction of
tolerance in autoimmune diseases.  In the case of rheumatic diseases
such as rheumatoid arthritis, delivery of genes to the synovial
membranes may induce significant local changes to reduce inflammation
and limit tissue destruction and disability.

Advantages include:  delivery of the active molecule to the optimal
site; high concentrations of therapeutic agent; continuous presence
of this molecule for days or weeks; and a defined end of exposure to
the molecule  (due to cellular turnover).  In experimental systems of
rheumatoid arthritis, the approach has shown promising results.

Research Objectives and Scope

While exciting advances have occurred in gene therapy, much of the
work has focused on hematologic cells or the cells of solid organs
and less effort has been focused on mucosal cells.  The main work in
the area concerns introducing the cystic fibrosis gene into
respiratory epithelial cells.  The aim of this RFA would be to
support basic research leading to gene transfer intended to augment
host defense at mucosal sites.  Relevant research includes, but is
not limited to, the following:

o  development and characterization of vectors that would efficiently
transfer genes into various cells of the respiratory,
gastrointestinal or genitourinary tracts and which are safe and
suitable for use in humans;

o  modification and packaging for transfection of genes that encode
molecules that are antimicrobials or anti-inflammatory and intended
to modify host/pathogen interactions;

o  modification and packaging for transfection of genes that are
useful as immunogenic or toleragenic epitopes for vaccines;

o  preclinical studies in cell lines and animal models that may prove
useful in evaluation of safety and efficacy of such approaches;

o  modification and packaging for transfection of genes to alter
mucosal levels of mediators specific or useful in the treatment of
asthma, inflammatory bowel disease and other immunologically mediated
disorders of unknown etiology.

NOTE:  This RFA is not intended to support studies of gene transfer
in genetic deficiencies.


It is the policy of the NIH that women and members of minority groups
their subpopulations must be included in all NIH- supported
biomedical and
behavioral research projects involving human subjects, unless a clear
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
(Section 492B of Public Law 103-43) and supersedes and strengthens
previous policies (Concerning the Inclusion of Women in Study
Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been
in effect since 1990.  The new policy contains some new 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
Research," which has been published in the Federal Register of March
28, 1994
(FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND
of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff
or contact person listed below.  Program staff may also provide
relevant information concerning the policy.


Prospective applicants are asked to submit, by July 15, 1995, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator, and the number and title of this RFA.
Although the letter of intent is not required, is not binding, does
not commit the sender to submit an application, and does not enter
into the review of subsequent applications, the information that it
contains allows NIH staff to estimate the potential review workload
and to avoid conflict of interest in the review.  The letter of
intent is to be sent to Dr. Christopher Beisel at the address listed


Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 9/91).  These application forms may be
obtained from the institution's office of sponsored research or its
equivalent and from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 5333 Westbard Avenue,
Room 449, Bethesda, MD 20892, telephone (301) 710-0267.

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

FIRST award (R29) applications must include at least three sealed
letters of reference attached to the face page
of the original application.  FIRST applications submitted without
required number of reference letters will be considered incomplete
and will be returned without review.

It is highly recommended that the appropriate NIAID or NIAMS program
contact be consulted before submitting the letter of intent and
during the early stages of preparation of the application.  (See
program contacts under INQUIRIES).

Submit a signed, typewritten original of the application, including
the checklist, and three signed, exact, single-sided photocopies, in
one package to:

Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express mail or courier service)

At the time of submission, two additional exact copies of the grant
application and all five sets of the appendix must also be sent to
Dr. Beisel at the address listed under INQUIRIES.

Applications must be received by November 15, 1995.  Applications
received after the receipt date will be returned without review.
Applications that do not conform to the instructions contained in PHS
398 (rev. 9/91) application kit will be judged non-responsive and
will be returned to the applicant.  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
exclude the submission of substantial revisions of an application
already reviewed.  These applications must, however, include an
introduction addressing the previous critique.

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 could be included
with the application.


Upon receipt, applications will be reviewed for completeness by the
NIH Division of Research Grants (DRG) and for responsiveness by NIAID
staff. Incomplete and non-responsive applications will be returned to
the applicant 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 by the NIAID in accordance with the review
criteria stated below.  As part of the initial merit review, a
process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non- competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the principal investigator and the official
signing for the applicant organization will be promptly notified.
The second level of review will be provided by the National Advisory
Allergy and Infectious Diseases Council and the National Arthritis
and Musculoskeletal and Skin Diseases Advisory Council.  Review,
Council and award dates can be found in "SCHEDULE", below.

Review Criteria

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

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

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

o  availability of the resources necessary to perform the research;

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

o  adequacy of plans to include 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

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.


Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program priorities, and
the availability of funds.


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

Direct inquiries regarding programmatic issues to:

Howard B. Dickler, M.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A19
6003 Executive Boulevard
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  hd7e@nih.gov

Susana A. Serrate-Sztein, M.D.
Rheumatic Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS37G
Bethesda, MD  20892-6500
Telephone:  (301) 594-5032
FAX:  (301) 480-4353
Email:  arthrit@ep.niams.nih.gov

Direct inquiries regarding review issues, mail two copies of the
application and all five sets of appendices, and mail the letter of
intent to:

Christopher E. Beisel, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C03
6003 Executive Boulevard
Bethesda, MD  20892-7610
Telephone:  (301) 402-4596
FAX:  (301) 402-2638
Email:  cb45d@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Maryellen Connell
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B28
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  mc40u@nih.gov


Letter of Intent Receipt Date:  July 15, 1995
Application Receipt Date:       November 15, 1995
Scientific Review Date:         March 1996
Advisory Council Date:          May 1996
Earliest Award Date:            August 1996


The program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 and No. 93.846.  Awards will be made under the
authority 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 CRF Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.

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 routing 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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