PILOT STUDIES TO DEVELOP NOVEL SYSTEMS FOR GENE DELIVERY Release Date: Febuary 11, 1998 PA NUMBER: PAR-98-026 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Mental Health Application Receipt Date: June 9, 1998 PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Mental Health (NIMH) invite applications for pilot and feasibility studies proposing innovative strategies for gene delivery that could ultimately lead to treatments for genetic metabolic diseases including cystic fibrosis. This program announcement replaces PAR-97-002 published October 18, 1996. This ongoing program is designed to permit investigators to obtain preliminary data on novel approaches to gene therapy. This program will be supported through the exploratory/developmental grant (R21) mechanism. Topics for this Program Announcement will be limited to pre-clinical studies designed to increase the level and the duration of gene expression in vivo. Research to elucidate the basic mechanisms and cellular factors involved in the processes of vector entry and gene expression will also be responsive to this program announcement. 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. 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 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. This program enables investigators to explore the feasibility of a concept related to gene therapy of metabolic diseases and generate sufficient data to pursue it through other funding mechanisms. The pilot and feasibility studies are intended to: (1) provide initial support for new investigators; (2) allow exploration of possible innovative new leads or new directions for established investigators in gene therapy; and (3) stimulate investigators from other areas to lend their expertise to research in this area. Pilot and feasibility grants are not intended to support or supplement ongoing funded research of an established investigator. MECHANISM OF SUPPORT This program will be supported through the exploratory/developmental grant (R21) mechanism. These awards are to demonstrate feasibility and obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants will not be renewable; continuation of projects developed under this program will be through the regular research project grant program. Projects will be limited to $100,000 direct costs per year and are limited to two years duration. The NIDDK has an ongoing program consisting of up to 10 awards each year. Funding of applications received in response to this Program Announcement will be contingent on the receipt of applications of sufficient scientific merit. RESEARCH OBJECTIVES Background Although the principle of delivering genes to a cell and repairing a defect in a metabolic pathway has been demonstrated in vitro, translating this basic finding into providing life-long correction to patients with genetic diseases has proven to be extremely difficult. In order to provide sustained correction, the gene must be delivered to either a non-dividing, long-lived cell or a stem cell that will continually transmit the gene to its progeny. Alternatively, transient correction could prove therapeutic if the regimen could be administered repeatedly. In both cases, it is necessary to avoid detection by the immune system, which recognizes the viral and sometimes the therapeutic protein as foreign, extinguishing their expression and producing antibodies, which interfere with readministration. The initial attempts at gene therapy for genetic metabolic diseases have revealed basic gaps in our knowledge on the mechanisms of vector entry, gene expression and immune surveillance. The vectors currently under investigation have a variety of properties that may be useful for some gene therapy applications. Viral vectors derived from adeno-associated virus, lentivirus and adenovirus can infect non-dividing cells and under some circumstances provide long-term expression. Retroviruses can transduce dividing cells and provide long-term expression but at low frequencies. Lipoplexes have provided mostly transient expression but may be amenable to strategies for targeted delivery and for evading the immune system. Other components such as the use of an appropriate promoter may be critical to the development of sustained, tissue-specific and/or regulated gene expression. Clearly, more work is needed to explore novel methods and novel combinations to develop regimens for long-term gene correction for genetic metabolic diseases. Delivery of genes to treat brain disorders poses unique problems. It requires efficient targeting of delivery vehicles across the blood-brain barrier to transfect fully differentiated, post-mitotic cells with a variety of phenotypes, as well as their multipotential progenitors. Direct administration of vectors into the brain may cause problems associated with cytotoxicity and physical tissue damages. For these reasons, development of efficient delivery methodologies, as well as the design and testing of appropriate promoters, may be critical to developmental patterns of tissue- or cell- type specific gene expression. The NIDDK initiated this Pilot and Feasibility Program in FY 1997 to provide a mechanism to fund innovative approaches to gene therapy applicable to genetic diseases. The NIDDK supports an integrated program of cystic fibrosis and metabolic disease research through regular research, program project, Specialized Centers of Research (P50), and Gene Therapy Core Center (P30) grants. NIMH supports research on delivery methodologies to target brain regions and nuclei that regulate cortical development and plasticity, emotion, cognition, memory, and behavior. Objectives The purpose of this Program Announcement is to allow investigators to test new approaches where there are limited preliminary data but a strong rationale and a reasonable expectation of feasibility. This limited award is designed to allow investigators to obtain the preliminary data necessary for a regular research grant. Applications for pilot projects and feasibility studies should be aimed at improving those aspects of gene therapy that are critical to ultimately treat genetic metabolic diseases by proposing either novel modifications of currently used vectors or development of novel systems for gene delivery. Areas of research emphasis include: o Developing new and non-conventional delivery systems; o Developing novel methods to extend the duration of transgene expression in vivo; o Developing novel methods for transduction of non-dividing cells; o Developing methods to improve transduction/transfection efficiency; o Developing methods to target vectors to specific cell types in vivo; o Developing methods to enhance efficiency of gene delivery across the blood-brain barrier; o Developing markers for selection of transduced cells in vivo; o Developing novel regimens for repeat administration of viral and non-viral vectors; o Developing new systems for regulated, inducible or cell-type specific gene expression encompassing the investigation of novel promoters, enhancers and locus control regions; o Developing methods for site-specific integration including more efficient methods of homologous integration; and o Determining the host cellular factors required for efficient vector entry, trafficking, integration, and expression. 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). 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 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 will be accepted on a single receipt date of June 9, 1998. Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). 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: asknih@od.nih.gov. The program announcement title, "Pilot Studies to Develop Novel Systems for Gene Delivery" and the number of this PA must be typed on line 2 of the face page of the application form and the YES box must be marked. Mail the signed, original, single-sided application, along with five exact, single-sided copies and five collated sets of appendix materials to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) The National Heart, Lung and Blood Institute; the National Cancer Institute; the National Institute of Child Health and Human Development; and the National Institute of Neurological Disorders and Stroke have an interest in supporting new approaches to gene therapy. Applicants interested in developing gene delivery systems applicable to the mission of these Institutes are encouraged to contact the appropriate program staff. If questions of program overlap arise for a given application, the PHS Referral Guidelines will prevail in the Institute assignment of the application. Some applications may receive multiple assignment. REVIEW CONSIDERATIONS Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIDDK in accordance with 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 The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written review, comments on the following aspects of the application will be made 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 in the assignment of the overall score. o 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? o Approach: Are 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? o 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? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Does this work represent a significant departure from the investigators ongoing funded research? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o 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? 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. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. 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 will compete for available funds with all other approved applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Mental Health. The following will be considered in making funding decisions: o Innovation o Quality of the proposed project as determined by peer review o Availability of funds o Program priority o Balance among the scientific areas covered by this program announcement. INQUIRIES Applicants are encouraged to discuss the relevance of their proposal to this program announcement prior to submission. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Catherine McKeon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 5AN.18B - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8810 FAX: (301) 480-3503 Email: Catherine_McKeon@nih.gov Steven O. Moldin, Ph.D. Division of Basic and Clinical Neuroscience Research National Institute of Mental Health 5600 Fishers Lane, Room 10C-26 Rockville, MD 20857 Telephone: (301) 443-2037 FAX: (301) 443-9890 Email: smoldin@nih.gov Direct inquiries regarding fiscal and administrative matters to: Ms. Denise Payne Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 BETHESDA, MD 20892-6600 Telephone: (301) 594-8845 Email: PayneD@extra.niddk.nih.gov Ms. Diana S. Trunnell Grants Management Branch National Institute of Mental Health 5600 Fishers Lane, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 (NIDDK) and 93.242 (NIMH). Awards are 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 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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