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Full Text AI-93-012


NIH GUIDE, Volume 22, Number 28, August 6, 1993

RFA:  AI-93-012

P.T. 34

  Immune System 
  Gene Therapy+ 

National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  October 27, 1993
Application Receipt Date:  December 8, 1993


The National Institute of Allergy and Infectious Diseases (NIAID) and
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invite Interactive Research Project Grant (IRPG) applications
for collaborative research efforts that combine immune reconstitution
and gene-based strategies to develop new treatment modalities for
HIV-1 infection.

The NIAID and NIDDK wish to promote research on: interactions of the
Human Immunodeficiency Virus-1 (HIV-1) with the immune system that
may impact on the immunologic reconstitution of infected individuals;
cytokines to facilitate stem cell reconstitution of HIV-infected
individuals or ameliorate/reverse HIV-related damage to the immune
system; and gene-based strategies to counteract detrimental effects
of HIV-1 on the immune system, to prevent infection of stem cells
transplanted into HIV-infected individuals, and to improve the
characteristics of ex vivo expanded lymphocytes to enable them to
function more effectively in vivo.  Although clinical trials will not
be supported under this Request for Applications (RFA), the basic and
preclinical research accomplished is expected to lay the foundation
for future clinical trials.

The NIAID and NIDDK request the coordinated submission of related
individual research project grant applications from investigators who
wish to collaborate on research, but do not require extensive shared
physical resources.  These applications must share a common theme and
describe the objectives and scientific importance of the interchange
of ideas, data, and materials among the collaborating investigators.
This collaborative research will be supported by
investigator-initiated Interactive Research Project Grant (IRPG)
awards.  For further information, potential applicants should refer
to the document, Special Instructions for Preparing Applications for
Interactive Research Project Grants.


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,
Immune Reconstitution of HIV-Infected Individuals, is related to the
priority area of HIV infection.  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 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.
Applications from minority individuals and women are encouraged.

Applicants for IRPGs may not concurrently submit additional R01
applications (either investigator-initiated or in response to another
RFA) that represent significant duplications of the efforts described
in the IRPG application.  Concurrent submission of program project
(P01) or cooperative agreement (U01) applications that request
support for essentially similar work is also prohibited.


The support mechanism for this RFA will be the individual research
project grant (R01) from investigators who wish to collaborate on
research efforts directed at the development of treatment strategies
utilizing immune reconstitution.  The independent research projects
will be organized into an IRPG that must consist of a minimum of two
independent R01 applications.

For this RFA, each IRPG group submission should include at least one
application proposing research on stem cell or somatic cell therapies
and one application proposing gene-based therapeutic strategies.
Each application must clearly identify the research that will be
carried out independently and that which will be carried out
collaboratively and include a succinct description of the scientific
relationships among the investigators and plans for collaboration,
interaction, and communication.  Refer to the document, Special
Instructions for the Preparation of Applications for Interactive
Research Project Grants.

An IRPG Coordinator should be identified from among the participating
R01 Principal Investigators.  Since the Coordinator will be
responsible for facilitating communication and collaboration among
the investigators, he/she may request a modest amount of funds for an
administrative core to support the time and effort contributed to
these activities.  See additional instructions on preparation of a
IRPG application.

All applicable PHS and NIH grants policies will apply to applications
received in response to this RFA.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of the awards will
vary also.  The budget request for the initial year's total costs
(direct and indirect) for the R01 applications in the IRPG group may
not exceed an average of $250,000 per R01 application.  (For example,
one application that requests $350,000 might be combined with two
applications requesting $200,000.)  Any budgets in excess of this
amount must be approved by the NIAID prior to submission of the IRPG
application.  Requests for expensive equipment are not encouraged.
Up to four years of support may be requested.

Reissuance of this RFA is anticipated but not certain.  If by the end
of the third year, the NIAID has not announced its intent to
re-advertise this RFA, incumbents should prepare unsolicited
competing continuation R01 or IRPG applications that will compete
with all investigator-initiated applications and will be reviewed by
traditional peer review procedures.  Those Principal Investigators
who wish to continue collaborative efforts should consult NIAID staff
before preparing their applications.


The NIAID and NIDDK anticipate awarding two to four IRPGs (a total of
six to eight R01 awards), for a total cost of $1.9 million for the
initial year of funding.  The NIAID has set aside $1.2 million for
applications received in response to this RFA, and the NIDDK has set
aside $0.7 million for this purpose.  These funding levels are
dependent on the receipt of a sufficient number of applications of
high scientific merit.



The mortality and morbidity suffered by HIV-infected individuals is
primarily the consequence of immune deficits that become increasingly
more severe during the course of the disease.  Several immune-based
strategies are presently under evaluation for ameliorating and/or
reversing immune deficiencies in HIV-infected individuals.  Prominent
among these are the use of HIV envelope vaccines or therapeutics
(e.g., interleukin-2) to augment existing responses to the virus or
enhance the immune system as a whole; HIV-specific lymphocytes or
antibodies to supplement the response elicited during the natural
course of infection; and bone marrow transplantation (BMT) to restore
immune cells lost as a result of HIV-1 infection.

BMT is currently being used to restore marrow function in cancer
patients whose hematopoietic systems have been ablated by chemo- and
radiation therapy.  The immediate goal is the reconstitution of
hematopoietic lineages required for acute survival, i.e., myeloid and
megakaryocyte lineages.  Less attention has been paid to the
restoration of the lymphoid lineage despite the fact that infectious
disease is responsible for a significant portion of the mortality in
survivors of BMT.  The CD4/CD8 T lymphocyte ratio may remain abnormal
for prolonged periods after transplantation, and persistent
functional deficits are evidenced by various in vitro assays of
immune function.

Basic information that bears on the feasibility of immune
reconstitution as a therapeutic approach for HIV infection is
currently incomplete.  For example, it is not known with certainty
whether or not human multipotent stem cells can be infected by HIV-1
and whether an HIV-1-infected host can provide the proper
physiological environment for the maturation of stem cells to their
respective differentiated lineages.  Further, it is not clear whether
a source of stem cells can be identified that meets the minimal
criteria for the success of a gene therapy utilizing stem cells,
namely the capacity to be maintained in vitro; to be modified to
resist HIV-1 infection; to home, differentiate and expand in vivo
after modification; and to retain the HIV-resistant phenotype in
differentiated lineages, particularly in T lymphocytes.

Human and animal model studies are currently assessing the capability
of CD34+ bone marrow cells to reconstitute a functional hematopoietic
system in appropriately conditioned recipients.  Other potential
sources of multipotent stem cells have been identified, including
fetal liver, yolk sac, and cord blood.  There is increasing evidence
to support the hypothesis that very primitive stem cells may possess
characteristics favorable to engraftment in a nonautologous setting
such that they may be able to persist without eliciting either a
graft versus host reaction or a host versus graft reaction.  Further
research is needed to confirm and amplify these findings.

Alternatively, the immune system might be temporarily supported in
the face of disease-related immunodeficiency by the transfer of
antigen-specific, ex vivo expanded lymphocytes.  Recent clinical
trials suggest that bone marrow transplant patients at risk of
cytomegalovirus-related disease might benefit from adoptive
immunotherapy with cytotoxic T cells that are capable of killing
virus-infected cells.  Animal and human studies are exploring a
possible role for HIV-specific T cells in controlling the infection.
Therefore, research on therapies that utilize cells with limited
capacity for in vivo expansion will be supported under this RFA
because of their potential utility in controlling HIV-1 in early
stage disease and in combatting opportunistic infections.

Goals and Objectives

The long term goal of this RFA is to provide an experimental basis
for using immune reconstitution as a therapy in individuals whose
immune systems are compromised by infectious disease.  This RFA
focuses on HIV/AIDS for which there is need for therapies that can
maintain/supplement the immune systems of infected individuals.
Since it is unlikely that HIV-1 can be totally eradicated from the
body by means presently available, strategies for the immune
reconstitution of HIV-infected individuals will require that the
transferred cells be genetically engineered to resist infection by,
and/or the damaging effects of, HIV-1.  Efforts are currently
underway to use gene-based strategies and immune reconstitution as
independent modalities to treat HIV-1 and associated infections.  The
objective of this RFA is to encourage preclinical research that
combines the two approaches through collaborative efforts among
independent investigators.

Research Scope

Research responsive to this RFA includes, but is not limited
to, the following:

Research to clarify interactions of HIV with the immune system that
may bear on the successful reconstitution of infected individuals

o  Mechanism(s) of destruction of lymphoid tissue by HIV-1 and
gene-based strategies for blocking mediators responsible for the

o  Effects of HIV infection on thymopoiesis and multilineage
engraftment of stem cells and gene-based strategies to counter
detrimental effects.

o  Aberrant T lymphocyte homeostasis in HIV-infected individuals or
in relevant animal models and gene-based therapies to normalize the
CD4/CD8 ratio.

o  Abnormal regulation of cytokine gene expression and gene- based
strategies for ameliorating the dysfunction of the cytokine network
in HIV-infected individuals.

Research on antiviral strategies

o  Design and evaluation of new gene-based antiviral strategies to be
used in stem cells or other sources of immune cells.

o  Effects of specific antiviral strategies on the biological program
of engineered multipotent stem cells.

o  Antiviral gene expression during differentiation of engineered
stem cells in vitro and in vivo.

o  Isolation, modification, and testing of antigen-specific, in vitro
expanded lymphocytes.  Modification includes the use of genetic
engineering to improve the potency, specificity, or other
characteristics of the cells to enable them to function more
effectively in vivo.

Developmental research

o  Development of novel sources of multipotent stem cells that can be
maintained in vitro and modified by genetic engineering techniques to
resist subsequent HIV infection and that are capable of
differentiating in vivo and retaining the HIV resistant phenotype in
the differentiated lineages.  Information bearing on the
transplantability of multipotent stem cells across allo- and
xeno-histocompatibility barriers is needed.

o  Discovery and characterization of cytokines, growth and/or
differentiation factors, particularly those capable of interacting
with T cell progenitors or their immediate antecedents.  The
discovery and development of new soluble factors are needed for the
in vitro maintenance of target cells for genetic engineering, to
provide sufficient material for evaluating the success and impact of
experimental anti-HIV strategies at an early point, and to stimulate
in vivo expansion of engineered stem cells.

o  Development of an in vitro colony forming assay for T cell
progenitors similar to those already in use for other hematopoietic
cell progenitors.  Existing methodologies for quantifying T cell
progenitor cells are time and labor intensive and measure progenitors
indirectly by quantifying their ability to repopulate the thymus in
animal models or to respond to mitogens in vitro.

While it is anticipated that complete development of new strategy for
immune reconstitution will not occur within the project period for
all groups, a rationale for the most likely use of discoveries made
or an outline of a plan for eventual clinical trials should be

Restrictions and Exclusions

Clinical trials will not be supported under this RFA.  However,
proposed analysis of samples acquired from NIAID-sponsored clinical
trials is appropriate.  Samples from ongoing trials may be made
available for specific experiments.  Budgetary limitations will
prohibit extensive use of primates in these projects (see MECHANISM
OF SUPPORT).  If a therapeutic strategy is developed to an advanced
stage under the RFA, every effort will be made to provide testing
through NIAID-supported primate resources.



Effective communication among IRPG investigators is very important.
IRPG investigators should plan to participate in one meeting per year
to be held alone or in conjunction with an NIAID-sponsored meeting
such as the National Cooperative Drug Discovery Group (NCDDG)
meeting.  Funds to support attendance at the meeting should be
included in each PI's budget.

Patent Coverage

Inasmuch as the development of effective treatment strategies is the
objective of this effort and since the active involvement by
industrial laboratories is facilitated by the existence of adequate
patent coverage, it is essential that applicants provide a plan,
agreed upon by the group, for obtaining patent coverage and for
licensing where appropriate.  In the event that the need for patent
coverage is anticipated, the grantee should contact program staff
listed under INQUIRIES well in advance of the application submission
deadline, who will provide the details of the patent requirements and
relevant regulations.  The NIAID will not be a partner in any patents
or royalties ensuing from this research.



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 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 must 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 in
Items 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, African Americans, Hispanics].  The
rationale for studies on single minority population groups must be

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 involving human subjects
also apply.  Basic research or clinical studies in which human
tissues cannot be identified or linked to individuals are excluded.
Every effort should be made to include 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.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in the 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

NOTE:  Peer review groups need adequate information about the
composition of proposed study populations in all applications
involving human subjects.  To avoid delays in review of such
applications, the NIAID therefore requires that, as a minimum, the
application must contain demographic data about the clinic and/or
in-patient population from which study subjects (including clinical
samples, materials, or fluids) will be drawn:  average hospital
admissions and/or clinic visits per year; percentage distribution of
black/hispanic/other minority/non-minority populations; gender; etc.
Studies using non-hospital populations, such as community-based
studies, should provide similar data about populations in the area or
region from which the study subjects will be drawn.  In the absence
of current data, historical demographic information and/or previous
recruitment data for similar studies from the proposed study sites
should be provided.


Prospective applicants are asked to submit, by October 27, 1993, a
letter of intent that includes descriptive titles of each proposed
research project in the IRPG group, the names and address of the
Principal Investigators and other key personnel, the participating
institutions, and the number and title of this RFA.

Although a letter of intent is not required, is not binding, and does
not enter into the review of the application, the information that it
contains is helpful in planning for the review of expected
applications.  It allows NIAID staff to estimate the potential
workload for reviewers and to avoid possible conflict of interest in
the review process.

The letter of intent is to be sent to Dr. Dianne Tingley at the
address listed under INQUIRIES.


Since applications that do not address the objectives of this RFA
will be considered nonresponsive and will be returned without review,
potential applicants are strongly encouraged to discuss their
research plans with program staff before completing their

Applications are to be submitted on the grant application form PHS
398 (rev. 9/91).  These forms are available at most institutional
offices of sponsored research and 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.

The RFA label available in the PHS 398 application kit must be
affixed to the bottom of the face page of the application.  To assure
the identification of your application with this RFA, the "Yes" box
must be marked in item 2a of the face page of the application and the
RFA number (RFA AI-93-012) and title IMMUNE RECONSTITUTION OF HIV-1
INFECTED INDIVIDUALS (IRPG) entered in the provided spaces in item
2a.  See the attached special instructions for further information on
application procedures.

The R01 applications constituting the proposed IRPG group must be
submitted in a single package, whether or not the applications
originate from the same institution.  Each application in the package
must be clearly identified and a cover letter must list the total
number of applications submitted for the IRPG, indicating the
Principal Investigator and title of each.  The various applications
should not be paginated or collated together like a Program Project,
since each R01 application will be processed individually and
assigned its own grant number by DRG, NIH.  For each application, the
original, three copies, and the appendix material must be put
together in one bundle and clearly identified.  Failure to follow the
instructions regarding submission date and packaging may lead to a
delay in review.

The IRPG package must be sent or delivered to:

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

At the time of submission to the Division of Research Grants (DRG),
also submit two additional exact copies of the IRPG applications
including appendices directly to Dr. Dianne Tingley at the address
listed under INQUIRIES.


Applications that have not followed the instructions for preparation
or that do not conform to the instructions contained in the PHS 398
(rev. 9/91) application kit will be judged incomplete and will be
returned to the applicant.  Each R01 application will be reviewed by
DRG staff for completeness and by NIAID and NIDDK staff to determine
responsiveness to this RFA; those individual or group applications
judged to be incomplete or non-responsive will be returned to the
applicant without review.  To be considered responsive, the
application should be directed towards the attainment of the stated
programmatic goals (RESEARCH OBJECTIVES).

Those applications that are complete and responsive may be subjected
to a triage before or during the initial scientific peer review by a
peer review group convened by the Division of Extramural Activities
(DEA), NIAID to determine their scientific merit relative to the
other applications received in response to this RFA.  The NIAID will
remove from further competition those applications judged to be
noncompetitive for award and will notify the applicant and
institutional business official.

Those applications judged to be competitive for award will be further
reviewed for scientific and technical merit by a review committee
convened by the Scientific Review Program, DEA, NIAID.  A second
level of review will be provided by the National Advisory Allergy and
Infectious Diseases Council and the National Diabetes and Digestive
and Kidney Diseases Advisory Council.  In the event of several highly
qualified applications, final funding recommendations will be based
on Program priorities.

Review Criteria

The factors considered in evaluating the scientific merit of each
application will be:

o  Scientific and technical merit of each individual R01 application,
including originality and feasibility of the approach;

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

o  Adequacy of plans for collaboration and communication with other
investigators in the IRPG group;

o  Adequacy of resources and environment (e.g., facilities and
equipment, shared interactive resources [cores]);

o  Experience, training, time commitment, and qualifications of the
investigators (a commitment of at least 15 percent is recommended for
Principal Investigators).

Review Procedures

Each R01 application will be reviewed independently for scientific
and technical merit.  Reviewers will read section 7 and will assess
the intended collaborations just as they do the proposed
collaborations in any other types of applications.  As appropriate,
the effectiveness and merit of the collaborations may contribute to
the overall assessment of the application.  In addition, budget
recommendations related to the appropriateness of shared interactive
resources (cores) will be reviewed for each application.
Recommendations concerning core(s) in an application will be
documented in administrative notes in the summary statements.  These
notes will assist the NIAID and NIDDK in making final decisions on
each application in the context of the overall IRPG.


The NIAID and NIDDK anticipate awarding two to four IRPG groups (six
to eight R01 awards total) as a result of this RFA.  The final number
and specific amounts of awards to be made will depend upon
consideration of the following:

o  Results of the initial scientific and technical merit review;
o  Potential contribution of the proposed research to the goals and
objectives of the RFA;
o  Program balance;
o  Availability of resources.


It is essential that prospective applicants carefully review the RFA
and the Special Insturctions for Preparing Applications for IRPGs
(available from program staff listed below).  NIAID and NIDDK staff
welcome the opportunity to clarify issues or answer questions from
potential applicants.

Direct inquiries regarding scientific issues or responsiveness to:

Dr. Sandra Bridges
Division of AIDS
National Institute of Allergy and Infectious Diseases
Solar Building, Room 2C12
Bethesda, MD  20892
Telephone:  (301) 496-8197

Dr. Ralph Bain
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A05
Bethesda, MD  20892
Telephone:  (301) 594-7556

Direct inquiries regarding the scientific review process, format of
applications, and address the letter of intent to:

Dr. Dianne Tingley
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C16
Bethesda, MD  20892
Telephone:  (301) 496-0818

Direct inquiries regarding fiscal matters and the format of
applications to:

Ms. Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B22
Bethesda, MD  20892
Telephone:  (301) 496-7075

Applicants who wish to use express mail or a courier service are
advised to follow the carrier's requirements for showing a street
address.  The address for the Solar Building is:  6003 Executive
Boulevard, Rockville, MD 20852


Letter of Intent Receipt Date:  October 27, 1993
Application Receipt Date:       December 8, 1993
Scientific Review Date:         March 1994
Advisory Council Date:          June 1994
Earliest Award Date:            July 1994


This program is described in the Catalog of Federal Domestic
Assistance, 93.856 - Microbiology and Infectious Diseases Research
and 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 Part 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.


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