Full Text PA-95-039

GENE TRANSFER FOR PRIMARY IMMUNE DEFICIENCY

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

PA NUMBER:  PA-95-039

P.T. 34

Keywords: 
  Gene Therapy+ 
  Immune System Disorders 


National Institute of Allergy and Infectious Diseases
The Jeffrey Modell Foundation

Application Receipt Dates:  June 1, and October 1, 1995 and February
1, 1996

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID) of
the National Institutes of Health (NIH) and the Jeffrey Modell
Foundation (JMF) invite investigator-initiated research grant
applications specifically targeted to isolation and characterization
of defective genes that cause primary immune deficiency diseases and
development of the techniques and vectors necessary to transfer these
genes into hematopoietic progenitors to correct the defects.

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 Program
Announcement (PA), Gene Transfer for Primary Immune Deficiency, is
related to the priority area of 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 20402-0325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) (R29) award.

MECHANISM(S) OF SUPPORT

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 PA may not exceed five
years; a foreign application may not request more than three years of
support.

FUNDS AVAILABLE

The estimated funds available for the total (direct and indirect)
first-year costs of awards made under this PA, for applications
assigned to the NIAID, will be $500,000 ($400,000 from the NIAID and
$100,000 from the JMF).  In Fiscal Year 1996, the NIAID and the JMF
plan to fund two to three R01 and/or R29 grants.  This level of
support is dependent on the receipt of a sufficient number of
applications of high scientific merit.  The usual PHS policies
governing grants administration and management, including indirect
costs, will apply.  Although this program is provided for in the
financial plans of the NIAID and the JMF, awards pursuant to this
program announcement 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.

New applications submitted for the June 1 and October 1, 1995 and
February 1, 1996 receipt dates will be eligible for funding under
this program announcement.  Competing continuation applications for
already funded projects will NOT be eligible for award from NIAID and
JMF under this PA.  Although the NIAID has a continuing interest in
the research areas of this PA, the latest anticipated award date with
set-aside funds is September 30, 1996.

RESEARCH OBJECTIVES

Background

Research on the immune system and diseases that result from
abnormalities of this system are part of the mission of the NIAID.
Primary immune deficiency diseases are a heterogenous group of
diseases in which immune system dysfunction causes such things as
abnormal susceptibility to infection and abnormal inflammatory
responses.  There are more than 70 such diseases (e.g.,
Wiscott-Aldrich Syndrome, Ataxia-telangiectasia, Bare Lymphocyte
Syndrome) and, although many are rare, it has been estimated that as
many as 500,000 individuals in the United States are affected, of
whom 5,000-10,000 (primarily children) are severely affected.  The
genes for most of these diseases have not yet been identified.
Morbidity, mortality, medical, and social costs for severely affected
individuals and their families are extremely high.  The Jeffrey
Modell Foundation was started by Vicki and Fred Modell in memory of
their son Jeffrey, who died in 1986, at the age of 15, of an
inherited immune deficiency.  This research foundation provides
funding to advance investigations, trials, diagnosis, and clinical
services needed for those with primary immunodeficiency diseases.

Advances in molecular biology and mapping the human genome provide
the opportunity to isolate and clone the defective genes that cause
primary immunodeficiency.  These advances include isolation of large
tracts of the human genome in cloned form, the development of novel
strategies to detect genes, and the use of efficient methods of
mutation detection.  A recent successful example involves cloning of
the gene responsible for x-linked agammaglobulinemia.  This gene is a
previously undescribed member of the SRC family of proto-oncogenes
which encode protein-tyrosine kinases.  Thus, not only has a gene
responsible for a disease been identified, but a whole new area in
tissue-specific signalling has been opened.

In addition, recent advances in isolation of hematopoietic
progenitors from peripheral blood greatly enhance the opportunity for
successful gene transfer for correction of the defects in patients
themselves.

Scope

The objective of this PA is to encourage innovative new research
targeted at isolation and characterization of the genes that cause
primary immune deficiency and development of the techniques and
vectors necessary for gene transfer to correct these defects.  Some
examples of research topics that would be considered responsive to
this solicitation include, but are not limited to, the following:

o  Application of advances in molecular biology and the human genome
map to isolate defective genes that cause primary immune deficiency.

o  Characterization of the structure and function of the products of
the defective genes and an indepth understanding of the biochemical
and immunologic consequences of the genetic defect.

o  Development of vectors for efficient and successful transfer of
normal versions of the genes that are defective in primary immune
deficiency.

o  Development or improvement of techniques for isolating and growing
hematopoietic progenitors and selecting those that have been
successfully transfected.

These areas of interest are not listed in any order or priority.
They are only suggested examples of areas of research.  Applicants
are encouraged to propose other areas that are related to the
objectives and scope of this PA as described above.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

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 is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and printed in
the NIH Guide for Grants and Contracts, Volume 23, Number 11, March
18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 9/91) and will be accepted on the standard application
deadlines as indicated in the application kit.  Requests for
continued funding of already funded projects (Type 2) will NOT be
considered under this program announcement.  Applications may be
submitted for the following receipt dates only:  June 1, and October
1, 1995 and February 1, 1996.  Awards resulting from this program
announcement will be made on or about April 1, July 1, and September
30, 1996.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.

Each application must be identified by checking "YES" on line 2a of
the PHS face page, and the number and title of this program
announcement must be typed in section 2a.

The completed original and five legible, single-sided copies of the
application must be sent or delivered 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)

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

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 Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
material.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be evaluated for scientific
and technical merit by an appropriate peer review group convened in
accordance with the standard 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, generally the top half
of applications under review, will be discussed, assigned a priority
score, and receive a second level review by the appropriate national
advisory council or board.

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
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.

AWARD CRITERIA

Applications assigned to the NIAID will compete for available
set-aside funds provided by the NIAID and the JMF.  The following
will be considered when making funding decisions:  quality of the
proposed project as determined by peer review, program balance among
research areas of the program announcement, and availability of
funds.

INQUIRIES

Written and telephone inquiries 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
Bethesda, MD  20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571
Email:  hd7e@nih.gov

Direct inquiries regarding fiscal matters to:

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

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.855 - Immunology, Allergy and Transplantation
Research.  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
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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