Full Text PAR-97-002 PILOT STUDIES ON GENE THERAPY VECTORS FOR METABOLIC DISEASES NIH GUIDE, Volume 25, Number 35, October 18, 1996 PA NUMBER: PAR-97-002 P.T. 34 Keywords: Metabolic Diseases Gene Therapy+ National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invites applications for pilot and feasibility studies proposing innovative strategies for gene therapy vector development. These grants will allow investigators to obtain preliminary data on novel approaches to gene therapy relevant to the treatment of genetic metabolic diseases. Topics for this Program Announcement will be limited to pre-clinical vector development designed to increase the level and the duration of gene expression in vivo. Research designed to elucidate the basic mechanisms and cellular factors involved in the processes of vector entry and transgene expression will also be responsive to this 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 nonprofit 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 This program will be supported through the exploratory/developmental grants (R21) mechanism. These awards are to demonstrate feasibility and obtain preliminary data. Thus, these grants will not be renewable; continuation of projects developed under this program will be through the research grant program. Projects will be limited to $100,000 direct costs per year and are limited to two years duration. The NIDDK anticipates initiating an ongoing program making five awards each year in response to this Program Announcement contingent on the receipt of applications of sufficient scientific merit. RESEARCH OBJECTIVES Background Gene therapy was originally envisioned as a method to permanently replace defective genes for the treatment of genetic diseases. To achieve this goal, a method of gene delivery must be efficient and have the ability to provide long-term, high-level expression in order to attain therapeutic levels of most proteins. Although many advances have been made toward this goal, none of the vector systems, retroviral, adenoviral or plasmids delivered by liposomes, currently being tested has all of these attributes. Research is needed to improve aspects of current vector systems as well as to investigate novel vector systems in order to make permanent genetic correction an attainable goal. On December 6, 1995, the NIDDK conducted a Workshop entitled, "AAV Vectors: Gene Transfer into Quiescent Cells." The Workshop explored the potential applications for one novel vector system, AAV, which exhibits many desirable characteristics for treatment of metabolic diseases. Many directions for future research were enumerated in this Workshop which have been summarized in a meeting report in Human Gene Therapy 7:1615-1619, 1996. Participants stressed the importance of studying vectors in vivo which often provides results different from those predicted by studies in cell lines. Although this Workshop was focused on AAV vectors, it served as a prototype for the problems encountered by investigators developing any new vector system. This Workshop identified the need for a mechanism to address research questions for new vector systems where feasibility had not yet been determined. Other examples of new vectors systems whose potential are being investigated for gene therapy include vectors based on Herpes Simplex virus, Epstein Barr virus, Lentivirus and Foamy virus. Last year the Director of NIH convened "The Panel To Assess the NIH Investment in Research on Gene Therapy." The members expressed their concern that new and novel methods need to be developed and this effort needs to be fostered by the NIH. They recommended the use of pilot and feasibility grants to help stimulate this process. The NIDDK currently supports pilot and feasibility studies associated with each of its funded Gene Therapy Centers. This Program Announcement would make a similar opportunity available to all investigators. 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. This limited award is designed to allow investigators to demonstrate feasibility and 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 which are critical for the treatment of genetic metabolic diseases by proposing either novel modifications of currently used vectors or novel vectors. Areas of emphasis for vector development include: o Improving the duration of transgene expression in vivo; o Improving capability of transducing 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 markers for selection of transduced cells in vivo; o Improving regulation and increasing levels of gene expression by the use 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 cellular factors required for vector entry, trafficking, integration, and expression. APPLICATION PROCEDURES Applications will be accepted at the standard application deadlines as indicated in the application kit. 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, or may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail: asknih@odrockm1.od.nih.gov. The program announcement title, "Pilot Studies on Gene Therapy Vectors for Metabolic Diseases" and number PAR-97-002 must be typed on line 2 of the face page of the application form and the YES box must be marked. The completed original application and five legible copies must be delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened by the 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 National Diabetes and Digestive and Kidney Diseases Advisory Council. The National Heart, Lung and Blood 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 these Institutes are encouraged to contact the appropriate program staff. If questions of program overlap arise for a given application, the DRG Referral Guidelines will prevail in the Institute assignment of the application. Some applications may receive multiple assignment. The following review criteria will be used to assess the scientific merit of an application: o novelty of the research proposed; o scientific, technical, or medical significance of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget for the proposed research; and 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. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Balance within the areas of research covered by the Program Announcement. INQUIRIES Applicants are encouraged to discuss the relevance of their proposal to this 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) 480-3508 Email: McKeonC@ep.niddk.nih.gov Direct inquiries regarding fiscal and administrative matters to: Donna Huggins Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 center Drive, Room 6AN-49K, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8848 Email: HugginsD@ep.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. 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 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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