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: https://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) 710-0267, 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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