DRUG DISCOVERY FOR OPPORTUNISTIC INFECTIONS ASSOCIATED WITH AIDS

NIH GUIDE, Volume 23, Number 33, September 16, 1994



PA NUMBER:  PA-94-095



P.T. 34



Keywords:

  AIDS 

  Drug Design 



National Institute of Allergy and Infectious Diseases



PURPOSE



The purpose of this Program Announcement (PA) is to solicit new

research grant applications aimed at novel approaches to discovery and

preclinical development of therapeutic agents active against

opportunistic infections in people with AIDS.  The research scope will

focus on basic and applied studies necessary to propel advances in

improved therapies.  The intent of this PA is to invite applications

for support of investigator-initiated research grants and the

Interactive Research Project Grants (IRPG) mechanisms.  No clinical

trials will be supported.



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, Drug

Discovery for Opportunistic Infections Associated with AIDS is related

to the priority area of human immunodeficiency virus /AIDS.  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. 017-001-00474-1) through the Superintendent of Documents,

Government Printing Office, Washington, DC 20402-9325 (telephone

202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, 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 may be submitted from one institution or may include

arrangements with several institutions, if appropriate.  Foreign

institutions are not eligible for First Independent Research Support

and Transition (FIRST) (R29) awards.  Applications from or involving

minority institutions, individuals, and women are encouraged.



MECHANISM OF SUPPORT



Support for this PA will be by the investigator-initiated research

project grant (R01), FIRST (R29) award, or the Interactive Research

Project Grants (IRPG) mechanisms.  If an IRPG is proposed, it must

consist of a minimum of two independent applications (see PA-94-086,

NIH Guide for Grants & Contracts,  Volume 23, Number 28, July 29,

1994).  An IRPG may consist of a combination of R01s and R29s or R01s

only, but may not consist solely of R29 applications.  An IRPG may also

contain shared interactive resources (Cores), which must serve at least

two of the research projects in order to facilitate achievement of the

Group's common research goals.  Collaborative arrangements involving

more than one institution are especially encouraged, including

participation of the pharmaceutical industry where appropriate.

Successful applicants in response to this PA will be invited to

participate in the National Cooperative Drug Discovery Groups for the

Treatment of Opportunistic Infections Associated with AIDS (NCDDG-OI)

program and annual meetings.  It is anticipated that awards made in

response to this program announcement are likely to provide the

foundation for subsequent drug discovery research sponsored through the

cooperative agreement mechanism.



RESEARCH OBJECTIVES



Background



Although HIV is the primary cause of the progressive immunological

deterioration seen in AIDS, the opportunistic infections (OIs) account

for the vast majority of all AIDS-related deaths as well as diminishing

quality of life.  Pathologic consequences associated with OIs in AIDS

are retinitis (cytomegalovirus), pulmonary disease (Pneumocystis

carinii), encephalitis (Toxoplasma gondii), meningitis (Cryptococcus

neoformans), tuberculosis (Mycobacterium tuberculosis), and

disseminated nontuberculosis mycobacterial disease (Mycobacterium

avium).  The management of OIs in AIDS patients is often difficult and

complicated due to:  (1) simultaneous infections with other OIs; (2)

toxicity and adverse side effects of therapeutic agents; (3) long-term

drug use leading to patient intolerance or pathogen drug resistance;

(4) occurrence of relapses after discontinuation of therapy; and (5)

lack of effective therapies for newly emerging OIs.



Objectives and scope



The objective of this PA is to stimulate drug discovery through

original and innovative research focused on key metabolic and

pathophysiologic features, which will lead to the development of safe,

well-tolerated, and effective new therapies for treatment and

prophylaxis of AIDS-associated OIs.  Applications based on sound

scientific rationale encompassing in vitro culture systems and/or

animal models to conduct the necessary preclinical studies are

encouraged.



The research scope encourages applications for studies on the following

pathogens: human cytomegalovirus (CMV), Mycobacterium tuberculosis,

Mycobacterium avium, Pneumocystis carinii, Toxoplasma gondii, and

Cryptococcus neoformans.  Innovative research focusing on other

particularly prevalent or problematic infections associated with AIDS

is also encouraged.  Areas of research may include, but are not limited

to, studies designed to:



o  Develop in vitro (culture) and in vivo (animal model) systems for

drug evaluations against one (or more) opportunistic pathogens.



o  Identify and characterize biochemical, metabolic and molecular

properties of the infectious organism that may serve as targets for

chemotherapy.



o  Discover new therapeutic agents or prophylactic approaches (e.g.,

chemo-, immuno-, or gene-based therapies) through exploitation of

biochemical, metabolic or molecular differences between pathogen and

host.



o  Discover new therapeutic agents through identification and

evaluation of promising natural  products and synthetic chemical

compounds, and elucidate their mechanism of action.



o  Elucidate mechanisms of drug resistance and study strategies to

overcome such resistance.



STUDY POPULATIONS



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 subpopulations 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 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

Clinical Research", which have been published in the Federal Register

of March 28, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE

FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.



APPLICATION PROCEDURES



Applications are to be submitted on form PHS 398 (rev. 9/91), the

standard application form for research grants.  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.  Receipt dates for

applications for AIDS-related research are January 2, May 1, and

September 1.  Applications must adhere to the format and requirements

specified in the PHS 398 application kit.



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.



For independent R01 or R29 applications, each application must be

identified by checking YES on line 2a of the PHS 398 face page, citing

this program announcement number.  If an IRPG is proposed, each

application must be identified along with the number of the program

announcement and the phrase "Investigator-initiated IRPG".  All R01 or

R29 applications constituting the proposed IRPG cohort must be

submitted in a single package, whether or not the applications arise

from the same institutions.  For detailed instructions for preparation

and submission of IRPG applications, refer to PA-94-086, NIH Guide for

Grants and Contracts, Volume 23, Number 28, July 29, 1994.



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.



Patent Coverage



Attention is drawn to the reporting requirements of 35 U.S.C. Parts

200-212 and 37 CFR Part 401 or FAR 55.227-11.  Instructions were also

published in the NIH Guide for Grants and Contracts, Vol. 19, No. 23,

June 22, 1990.  Note that non-profit organizations (including

universities) and small business firms retain the rights to any patent

resulting from Government contracts, grants or cooperative agreements.



It is also noted that a Presidential memorandum of February 18, 1983

extended to all business concerns, regardless of size, the first option

to the ownership of rights to inventions as provided in P.L. 96-517.

As a result of this memorandum, the relationships among industrial

organizations and other participants are simplified, since all Group

members can now be full partners in the research and in any inventions

resulting therefrom.  The specific patenting arrangements among

institutions may vary, and could include joint patent ownership,

exclusive licensing arrangements, etc.  Applicants are encouraged to

develop an arrangement that is most suitable for their own particular

circumstances.



Federal regulation clause 37 CFR 401 and HHS Inventions regulations at

45 CFR Parts 6 and 8 require that NIH be informed of inventions and

licensing occurring under NIH funded research.  Invention and licensing

reports must be submitted to Extramural Invention Reports Office,

Office of Extramural Research, Building 31, Room 5B41, NIH, 9000

Rockville Pike, Bethesda, Maryland 20892.



The completed original application and five legible copies must be sent

or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW CONSIDERATIONS



Upon receipt, applications and supporting material will be examined by

the Division of Research Grants for completeness.  Incomplete

applications will be returned without further consideration.



Applications will be assigned on the basis of established Public Health

Service referral guidelines.  Applications will be reviewed

independently for scientific and technical merit by study sections of

the Division of Research Grants, NIH, in accordance with the standard

NIH peer review procedures.



Review criteria are:



o  Significance and originality of the research and methodological

approaches.

o  Feasibility of the research and adequacy of the experimental design.

o  Interactive nature of the program and of the component IRPGs (where

applicable).

o  Training, experience, research competence and commitment of the

investigator(s).

o  Adequacy of the facilities and resources.

o  Provisions for the protection of human subjects, the humane care of

animals, and biosafety conditions.



Following scientific and technical merit review, applications will

receive a second level review by the appropriate National Advisory

Council(s).



AWARD CRITERIA



Applications will compete for available funds with all other

applications found to have significant and substantial merit.  The

following will be considered in making funding decisions:



o  Quality of the proposed project as determined by peer review.

o  If an IRPG is proposed, the interactive nature of the program and of

the component IRPGs as determined by peer review.

o  Availability of funds.

o  Program balance among research areas.



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

Written instructions for the preparation of IRPG applications are

available upon written request.  This document, "Special Instructions

for Preparing Applications for Investigator-Initiated Interactive

Research Project Grants," is available from the Office of Grants

Information, Division of Research Grants, NIH, 301-710-0267.



Direct inquiries regarding programmatic issues to:



Dr. Barbara Laughon

Division of AIDS

National Institute of Allergy and Infectious Diseases

Solar Building, Room 2C26

6003 Executive Boulevard, MSC 7620

Bethesda, MD  20892-7620

Telephone:  (301) 402-2304

FAX:  (301) 402-3211

Email:  barbara_laughon@nih.gov



Direct inquiries regarding fiscal matters to:



Ms. Pamela Greenwald

Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B22

6003 Executive Boulevard, MSC 7610

Bethesda, MD  20892-7610

Telephone:  (301) 496-7075

FAX:  (301) 480-3780



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic Assistance

No 93.856, Microbiology and Infectious Diseases Research.  Grants are

awarded under the authority of the Public Health Service Act, Section

301 (42 USC 241) and administered under the PHS grants policies and

Federal Regulations, most specifically at 42 CFR Part 52 and 45 CFR

Part 74.  This program is not subject to the intergovernmental review

requirements of the Executive Order 12372 or Health Systems Agency

review.



.

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