HIV THERAPEUTICS: TARGETING RESEARCH GAPS

Release Date:  March 4, 1999  

PA NUMBER:  PA-99-067

P.T.

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

PURPOSE

The National Institute of Allergy and Infectious Diseases (NIAID), National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and National
Institute of Mental Health (NIMH), National Institutes of Health (NIH), invite
applications to conduct applied studies in specific gap areas identified in
current HIV therapeutics.  Therapeutic gap areas identified for studies under
this PA include: (1) new delivery or formulation methods to enhance the
clinical potential of anti-HIV drugs (FDA-approved or those undergoing
clinical testing) in infected adults and children; (2) validating new viral
and cellular targets for HIV inhibition and for developing new drugs (or
developing new agents against existing targets); and (3) defining and
validating the role of innate (non-acquired) immune responses in
susceptibility to HIV infection, modulation of disease progression, and their
potential use in therapeutic application in infected adults and children.
Studies targeted in this Program Announcement should generate preclinical
proof-of-concept on the therapeutic feasibility of the specific target or
approach, and engage in applied preclinical studies that accelerate the entry
of the target/approach to the therapeutic R&D pipeline.  When relevant,
applications with clinical studies (e.g., evaluating a drug delivery method)
will be considered.

Applicants for Small Business Innovation Research (SBIR) projects on
investigational areas included in this PA should consider applying through
NIAID PAR-98-073, published in the NIH Guide for Grants and Contracts on May
22, 1998.  NIAID PAR-98-073 is available on the World Wide Web at:
http://www.nih.gov/grants/guide/pa-files/PAR-98-073.html

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 PA, HIV Therapeutics: Targeting
Research Gaps, 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 Summary Report: Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC 20402-
9325 (telephone 202-512-1800).

ELIGIBILITY

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.

MECHANISM OF SUPPORT

Traditional research project grant (R01) applications may be submitted in
response to this program announcement.  Applications for R01 grants may
request up to five years of support.  Responsibility for the planning,
direction, and execution of the proposed research will be solely that of the
applicant.

RESEARCH OBJECTIVES

Background

The intense effort over the years in HIV therapeutics has paid off: critical
viral enzymes (RT, PR) were defined, inhibitors identified, and lead compounds
optimized and translated to clinically approved drugs. Combined anti-RT/PR
therapies (highly active antiretroviral therapies, or HAART) have resulted in
reduced hospitalization, decreased incidence of opportunistic infections,
lessened mortality, and improved the quality of life of HIV-infected
individuals.  The suppression of HIV has also led to partial improvement in
immune functions.  However, problems with current HIV therapeutics persist. 
Among these are inadequate pharmacology (bioavailability, tissue distribution,
others), emergence of drug resistant HIV variants, adverse effects, metabolic
abnormalities and toxicities, poor adherence to complex, multi-drug regimens,
and primary infection with drug-resistant and multi-resistant HIV variants.
Thus, therapeutics discovery and development remains a critical activity. To
address these problems and to expand the therapeutics pipeline, specific gap
areas were identified for applied studies under this PA.  These applied areas
respond to and address emerging issues in HIV therapeutics, and capitalize on
new therapeutic and technological opportunities that are supported by a broad
foundation of basic research.

Research Objectives and Scope

The specific objectives identified for this PA include studies that are aimed
to:
Objective 1: To develop/deploy new delivery (or formulation) methods to
enhance the clinical potential of anti-HIV drugs (FDA-approved or undergoing
clinical testing) for HIV infected adult & pediatric patients.

The use of alternative delivery technology (mini pumps, dermal patches, new
formulation) may significantly improve the clinical pharmacology of current
therapeutic regimens. This PA supports the development, application, and
evaluation of new drug delivery technologies to minimize the multiple problems
seen with HAART (inadequate pharmacology, tissue distribution, emergence of
drug resistant variants, metabolic abnormalities, toxicities, adherence,
others) with the ultimate goal of reaping the full clinical potential of
existing and new anti-HIV drugs.

Studies related to this objective may include, but are not limited to the
following:
o  Exploit new technologies and application of delivery devices and
formulations that improve the efficacy of HIV therapeutics
o  Conduct preclinical feasibility studies in relevant animal models
o  When relevant, clinical evaluation in humans through partnership with the
pharmaceutical sector or with other clinical networks is encouraged.

Objective 2: To validate new therapeutic viral and cellular targets for the
development of new inhibitory agents.

The dramatic reduction in viral load and clinical improvements achieved with
HAART is a rigorous validation of the ability of anti-HIV drugs to contain and
manage HIV-disease, and demonstrates that combination of 3 or more anti-HIV
agents - even when directed against only 2 of the putative 10 viral targets -
are superior to single or dual drug therapy.  Thus, the prevailing belief is
that the addition of new anti-HIV agents to HAART regimens will provide
additional clinical benefits.  New agents are also critically needed to treat
HIV-infected patients that have become intolerant to existing drugs. Viral
elements and cellular co-factors required for HIV activity represent unique
targets for viral inhibition and for expansion of the therapeutics pipeline.

Studies related to this objective may include but are not limited to the
following:
o  Validate the relevance of identified targets for therapeutic intervention;
obtain preclinical proof-of-concept for the role of the target in HIV
growth/pathogenesis
o  Employ new assays and technologies to identify inhibitors of the specific
target
o  Deploy relevant lentivirus animal models or transgenic models to test
therapeutic candidates against highly conserved targets (e.g., Rev, Nef).

Objective 3: To define and validate the role of innate immune components /
responses in susceptibility to HIV infection, modulation of disease
progression, and their potential use in therapeutic application in adults and
pediatric patients.

Little is known about the role of antigen non-specific cells (natural killer
cells, phagocytic cells, gamma / delta T cells), pattern recognition receptors
(PRR) and regulation of co-stimulatory signals in acquired immunity, and non-
specific effector molecules (complement) in the clearance of HIV and/or in
their contribution to pathogenic processes during disease progression. This PA
supports studies on the relevance and manipulation of the innate immune
components in HIV-infected individuals or appropriate animal models.  Such
studies are expected to lead to the development of new therapeutic strategies
and vaccine designs.

Studies related to this objective may include, but are not limited to the
following:
o  Establish whether innate immunity can be modulated to control virus growth
and/or reinforce acquired (Ag-specific) immune based therapies
o  Establish preclinical proof-of-concept of the contribution of innate
immunity in appropriate in vitro and in vivo systems (lentivirus animal
models; clinical specimens)
o  Establish whether innate immune components can be used as surrogate
indicators of the effectiveness of antiviral therapies.

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,
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 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical
Research", published in the Federal Register of March 28, 1994 (FR 59 14508-
14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18,
1994 which is available on the web at:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and which is available at the following
URL address:  http://www.nih.gov/grants/guide/notice-files/not98-024.html

Investigators may obtain copies from these sources or from Dr. Nava Sarver
(listed in INQUIRIES below) who may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted on the standard AIDS-related application deadlines
as indicated in the application kit.  Application 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: grantsinfo@nih.gov. Application kits are also available
on the World Wide Web at http://www.nih.gov/grants/forms.htm.

For purposes of identification and processing, item 2 on the face page of the
application must be marked "YES". The PA number and the PA title must also be
typed in section 2.

The completed, signed original and five legible, single-sided copies of the
application and five copies of appendices must be sent or delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817-7710 (for express/courier service)

Applicants from institutions that have a General Clinical Research Centers
(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

Review Procedures

Applications will be assigned on the basis of established PHS referral
guidelines.  Upon receipt, applications will be reviewed for completeness by
the NIH Center for Scientific Review.  Incomplete applications will be
returned to the applicant without further consideration.

Applications will be reviewed for scientific and technical merit by study
sections of the Center for Scientific Review, NIH, 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 the applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate national
advisory council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.  Note that
the application does not need to be strong in all categories to be judged
likely to have a major scientific impact and thus deserve a high priority
score.  For example, an investigator may propose to carry out important work
that by its nature is not innovative but is essential to move a field forward.

1.  Significance.  Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

2.  Approach.  Is the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator.  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups, and children as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects;
the provisions for the protection of human and animal subjects; and the safety
of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other favorably
recommended applications.  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 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.\

Inquiries regarding programmatic (research scope and eligibility) issues may
be directed to:

Nava Sarver, PhD
Division of AIDS
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 2C01
Bethesda, MD  20892-7640
Telephone:  (301) 496-2970
FAX:  (301) 402-3211
Email:  ns18p@nih.gov

Inquiries regarding programmatic issues related to the identification of new
drugs or improved formulation methods that target HIV in the CNS may be
directed to:

Dianne Rausch, Ph.D.
Office of AIDS Research
National Institute of Mental Health
6001 Executive Boulevard, Room 6209, MSC 9619
Bethesda, MD 20892-9619
Telephone:  (301) 443-7281
FAX :(301) 443-9719
Email: dr89b@nih.gov

Inquiries regarding programmatic issues related to mitigate metabolic adverse
effects of HIV drugs and address intestinal/digestive tract absorption and
liver metabolism may be directed to:

Philip F. Smith, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8816
FAX: (301) 480-3503
Email: ps56z@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Mollie Shea
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Solar Building, Room 4B26
Bethesda, MD 20892-7610
Telephone: (301) 402-6576
Email: ms256g@nih.gov

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
FAX:  (301) 443-6885
Email: Diana_Trunnell@nih.gov

Kieran Kelley
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-0417
FAX: (301) 480-3504
Email: kk27g@nih.gov

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health Service
Act, Sec. 301 (c), Public Law 78-410, as amended.  The Catalogue of Federal
Domestic Assistance Citations are Sec. 93.856, Microbiology and Infectious
Diseases Research, and No. 93.855 - Immunology, Allergy, and Transplantation
Research.  Awards will be 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 review.

The Public Health Service 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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