RFA-DK-02-020: GENE TRANSFER APPROACHES TO ENHANCE ISLET TRANSPLANTATION

Department of Health
and Human Services (HHS)

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GENE TRANSFER APPROACHES TO ENHANCE ISLET TRANSPLANTATION Release Date: September 20, 2001 RFA: RFA-DK-02-020 National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov/) National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov/) Letter of Intent Receipt Date: November 15, 2001 Application Receipt Date: December 12, 2001 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases are soliciting applications to develop gene transfer approaches to enhance islet transplantation. Type 1 diabetes results from the immune destruction of the pancreatic beta-cell. Several protocols are being tested that treat this disease by transplantation of islets. One of the major barriers to implementing this approach is the limited supply of islets for transplantation. Ex vivo gene transfer approaches could be one method to engineer beta-cells or alter islets to enhance viability that could have advantages for transplantation. NIDDK and NIAID are soliciting pilot and feasibility grants to explore gene transfer techniques that could be applied to enhanced islet transplantation. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Request for Applications (RFA), Gene Transfer Approaches to Enhance Islet Transplantation, is related to the priority area of Diabetes and Chronic Disabling Conditions. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. 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. This program enables investigators to explore the feasibility of a concept related to gene therapy of diabetes 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 RFA will use the National Institutes of Health (NIH) exploratory/developmental grant (R21) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 2 years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2002. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NIDDK and NIAID intend to commit approximately $2,000,000, provided for research on type 1 diabetes by Section 931 of the Benefits Improvement and Protection Act of 2000, in FY 2002 to fund 10 to 12 new grants in response to this RFA. An applicant may request a project period of up to 2 years and a budget for direct costs of up to $100,000 per year, including indirect (Facilities and Administration) costs on consortium arrangements. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIDDK and NIAID provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Type 1 diabetes is estimated to affect 1 million Americans many of them children. These individuals must adhere to a regimen of life-long dietary restriction, glucose monitoring and insulin administration and even the most rigorous effort is not sufficient to normalize glucose levels. Major mortality and morbidity are from the long-term complications of the disease including blindness, neuropathy, renal and cardiovascular disease. Recently, promising results have been achieved in a several patients with islet transplantation using a new combination of drugs that prevent rejection and halt autoimmune destruction of transplanted islets. While these results are promising, the long-term toxicity of these drugs is unknown and a major obstacle to the wide-spread application of this treatment is the limited supply of islets. Novel approaches are needed to develop new sources of beta-cells or islets for transplantation and to enhance their viability. Gene transfer is one method that can be used to alter the properties of somatic cells. Recently, several viral vectors, especially the lentiviral and AAV vectors, have shown promise for introducing genes into beta-cells. Using these gene transfer techniques, beta-cells with new properties can be developed to enhance transplantation. Objectives and Scope Several possible approaches could be used to alter the properties of cells to develop islets for transplantation. One approach is to engineer beta-cells with regulated growth promoting genes to permit expansion in vitro. Human beta-cell lines have been developed using the oncogenes, SV40 T antigen and H-ras. However, these lines are unlikely to be suitable for clinical use because of the presence of the oncogene. An elegant technique has been described in hepatocytes to excise the growth promoting oncogene prior to transplantation using a cre/lox site-specific recombination system. Similar approaches could be applied to beta-cells Another potential source of beta-cells is to derive beta-cells from other tissues by introducing genes that induce transdifferentiation of beta-cells. For example, the expression of PDX1 in hepatocytes and exocrine pancreas results in markers of beta-cell differentiation. This approach could facilitate the establishment of beta-cells from cells that already grow well in culture. Recently, hematopoietic stem cells have demonstrated greater plasticity to develop along other lineages than previously believed. These would also be a source of cells that may be able to be manipulated to differentiate to beta-cells by expressing genes that control the developmental program. In addition, the beta-cells could be engineered to be more resistant to immune destructive and apoptotic signals prior to transplantation. This could reduce the number of cells that need to be transplanted as well as reduce the need for immunosuppression. Modification of the histocompatibility markers on beta-cells would result in cells that generate a reduced immune response. Using gene transfer techniques to blocking apoptotic pathways could produce beta-cells that have a survival advantage after transplantation. Another approach to reducing the number of beta-cells needed is to introduce a gene that could be used to apply selective pressure to give transplanted beta- cells a selective growth advantage in vivo. In addition to altering the properties of the transplanted cells, gene transfer techniques could be used to modulated the immune system of the subject prior to transplantation. Most patients with type 1 diabetes have developed antibodies to beta cell markers. Gene transfer techniques can be used to induce tolerance for beta-cell markers or to alter immune regulatory cells to reduce the risk of transplant rejections. Since these are preliminary studies to explore the appropriate use of this new technology and to demonstrate its feasibility, the NIDDK and NIAID are using the exploratory/developmental grant mechanism. These grants can be used to demonstrate the feasibility of an approach and to develop preliminary data for a future regular research grant submission. This mechanism allows investigators to test new approaches where there are limited preliminary data but a strong rationale and a reasonable expectation of feasibility. Some of the approaches that need to be explored are enumerated below. Relevant topics listed below are only examples and should not be construed as required or limiting: o Investigate the use of growth promoting genes to derive beta-cells that can be expanded in culture while maintaining or reintroducing the differentiated phenotype for transplantation. o Derive beta-cells from other tissues or progenitor cells by introducing genes needed to develop the differentiated beta-cell phenotype. o Engineer beta-cells that have enhanced resistance to immune destructive or apoptotic signals. o Engineer beta-cells that elicit a reduced or altered immune response. o Investigate the use of gene transfer for immunomodulation to reduce the need for immunosuppression and reduce islet transplant rejection 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 and compelling rationale and justification are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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 is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the policy that was published in the NIH Guide for Grants an Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit, by November 15, 2001, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIDDK staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. Although applicants are strongly encouraged to begin using the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue to accept applications prepared using the 4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov. All application instructions outlined in the PHS 398 (rev. 5/01) application kit are to be followed, with the following modifications: 1. Applicants MUST cite the RFA number on line 2 of the application. Applicants are strongly urged to contact the Program Directors listed in the INQUIRIES section prior to submission of an application, for advice about eligibility and responsiveness. 2. R21 applications will use the MODULAR GRANT and JUST-IN-TIME concepts, with direct costs requested in $25,000 modules, up to the total direct costs limit of $100,000 per year. 3. Although preliminary data are not required for an R21 application, they may be included. 4. Sections a-d of the Research Plan may not exceed 15 pages, including tables and figures. 5. Appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 15 page limit of items a-d of the research plan. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step-by-step instructions for Modular Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm. Additional information about Modular Grants is also available on this site. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package 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) At time of submission, two additional copies of the application must be sent to: Chief, Review Branch Division of Extramural Activities, NIDDK 6707 Democracy Boulevard, Rm. 752 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Applications must be received by the application receipt date listed in the heading of the RFA. If an application is received after that date, it will be returned to the applicant without review. Supplemental documents containing significant revision or additions will not be accepted, unless applicants are notified by the Scientific Review Administrator. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIDDK or CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in the competition with unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIDDK in accordance with the review criteria stated below. 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 National Diabetes and Digestive and Kidney Diseases 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. In the written comments, reviewers will be asked to discuss the following aspects of the application 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 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 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: 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? (3) Innovation: Does the project employ novel concepts, approaches or methods? 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o Adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. 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. Schedule Letter of Intent Receipt Date: November 15, 2001 Application Receipt Date: December 12, 2001 Peer Review Date: February 2002 Council Review: May 30-31, 2002 Earliest Anticipated Start Date: July 1, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit as determined by peer review, o Availability of funds, o Programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. 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 6707 Democracy Boulevard, Rm. 6103 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8810 FAX: (301) 480-3503 E-mail: cm67w@nih.gov Shiv A. Prasad, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Dr., Room 5255 Bethesda, MD 20892-7640 (20817 for express mail deliveries) Telephone: (301) 496-5598 FAX: (301) 402-2571 Email: sp89j@nih.gov Direct inquiries regarding fiscal matters to: Mary Kay Rosenberg National Institute of Diabetes and Digestive and Kidney Diseases Division of Extramural Activities 6707 Democracy Boulevard, Rm. 722 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8891 FAX: (301) 480-3504 E-mail: mr239s@nih.gov Pamela G. Fleming Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6700-B Rockledge Dr., Room 2119 Bethesda, MD 20892-7614 Use Zip Code 20817 for overnight deliveries Telephone: (301) 402-6580 FAX: (301) 480-3780 Email: pf49e@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847 and 93.855. 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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