RFA-DK-01-006: GENE THERAPY APPROACHES FOR DIABETES AND ITS COMPLICATIONS

Department of Health
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GENE THERAPY APPROACHES FOR DIABETES AND ITS COMPLICATIONS Release Date: August 30, 2000 RFA: DK-01-006 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/ National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/ Letter of Intent Receipt Date: October 16, 2000 Application Receipt Date: November 16, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute are soliciting applications to develop gene therapy approaches for the treatment of diabetes and/or its complications. Gene therapy is a promising technology to introduce exogenous genes into somatic cells that will alter the cell’s properties. On November 8 and 9, 1999, the NIDDK and NIAID along with other Institutes sponsored a meeting entitled, Gene Therapy Approaches for Diabetes and Its Complications, to discuss possible approaches for using gene therapy to treat either diabetes or its complications. One of the recommendations from the meeting was to support additional studies to develop novel approaches using gene therapy for the treatment of diabetes and its complications. 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 Therapy Approaches for Diabetes and Its Complications, is related to the priority areas 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. 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. This RFA is a one-time solicitation. These grants are not renewable; continuation of projects developed under this program will be through the regular research grant program and will compete with all investigator- initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2001. FUNDS AVAILABLE The NIDDK, NIAID, and NHLBI intend to commit a total of approximately $2,000,000 ($1,000,000 from the Balanced Budget Act of 1997 and $1,000,000 from the NIDDK appropriation) in FY 2001 to fund 12 to 15 new grants in response to this RFA. Although the financial plans of the NIDDK, NIAID, and NHLBI 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. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background Over the last ten years, gene therapy techniques have been developed for introducing genes into somatic cells that alter the properties of these cells. Recently, several successful reports suggest that gene therapy may be an appropriate treatment for certain conditions. There are many approaches to interfering with the development of type 1 diabetes and to treating the complications resulting from both type 1 and type 2 diabetes that would appear to be amenable to gene therapy technology. The purpose of this RFA is to encourage development of gene therapy approaches for type 1 diabetes and its complications and to test these in appropriate animal models or small pilot studies. On November 8 and 9, 1999, the NIDDK, NIAID, NHLBI, NCRR, JDFI and ADA sponsored a meeting entitled, Gene Therapy Approaches for Diabetes and Its Complications, to discuss some possible approaches for using gene therapy to treat either diabetes or its complications. The Summary and Recommendations from that conference can be found on the NIDDK Web page at http://www.niddk.nih.gov/fund/divisions/DEM/DEMintro.htm. One of the recommendations from that meeting was to support the development of additional approaches using gene therapy for the treatment of diabetes and its complications. Since these are preliminary studies to explore the appropriate use of this new technology and to demonstrate its feasibility, the NIDDK is 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. Type 1 diabetes results from the immune destruction of the beta cells in the pancreas. Therefore, methods that interfere with the development of autoimmunity or the immuno-destructive process would prevent the development of type 1 diabetes. There seems to be sufficient understanding of type 1 diabetes immune mediated beta-cell killing to devise gene therapy approaches that interrupt the inflammatory process. It may also be possible to interfere directly with the apoptotic pathways within the beta cell that result in its death. This use of gene therapy will not correct a defective genetic makeup but rather will interrupt the progression of disease pathogenesis. Fundamental research could focus on induction of immunologic tolerance. For example, DNA-based vaccine approaches should be explored as a method of providing expression of autoantigens to induce tolerance. Preclinical work has already tested the hypothesis that the genetic manipulation to express autoantigens will reduce beta-cell self reactivity. This approach would be applicable to prevention of type 1 diabetes. Gene therapy can be applied as an intervention for type 1 diabetes. Research utilizing T cell homing technologies to deliver immune suppressive cytokines or other factors at the site of the inflammation is a very exciting prospect. This is an important area of research that may yield therapeutic modalities that would interfere with progressive inflammatory diseases, including beta-cell killing in type 1 diabetes. It would seem that the antigen or epitope specificity of the immune system with respect to the use of either antibodies, T cells or both has not been fully explored for disease protection and inhibition of progressive autoimmunity diseases. The gene therapy technology would involve both ex vivo and in vivo approaches. Another potential approach to prevent the development of diabetes is to prevent apoptosis of the beta-cell by targeting protective genes into the pancreas in vivo. These could include tissue-specific expression of immune suppressive cytokines and apoptotic genes. These techniques could also be employed to protect transplanted pancreatic beta-cells or transplanted islets from autoimmune destruction, allograft rejection or both. Ongoing research at the preclinical level suggests that islets expressing certain ligands or immune suppressive cytokines have an improved survival. This is a novel and hitherto uncharted area of research that deserves further exploration. Recently, a novel approach of generating beta cells in vivo has been tested in an animal model. The introduction of the transcription factor, PDX1, into hepatocytes resulted in the transdifferentiation of hepatocytes to beta-cells (Nature Medicine 6:568-572, 2000). The exploration of this and other transdifferentiation strategies may also yield novel ways to treat type 1 diabetes. Long-term complications of diabetes include nephropathy, retinopathy, neuropathy, accelerated cardiovascular disease, impaired wound healing, altered gastrointestinal and bladder function, and periodontal disease. Since glucose management remains a difficult problem, complications from diabetes continue to be a high priority area for development of novel treatments. Gene therapy approaches seem promising in the selected areas of micro and macro vascular disease, neuropathy and wound healing. Several of these studies are progressing to phase I clinical trials. One approach expressed the growth factor, VEGF, locally to grow new blood vessels for the treatment of vascular disease. Another approach used the introduction of the growth factor, PDGF, into diabetic ulcers to accelerate wound healing. These and other gene therapy approaches to treat these conditions need to be explored. Scope and Objectives Applications should focus on the development of gene therapy approaches for the treatment of type 1 diabetes and its complications. Although delivery of insulin by gene therapy is one possible method to treat diabetes, this approach is complicated by the requirement for rapid and tight regulation of insulin secretion to glucose levels. Such studies may be premature with our current technology. Relevant topics listed below are examples and should not be construed as required or limiting. o To investigate gene therapy strategies to induce tolerance to beta-cell antigens o To investigate novel strategies such as T-cell homing to deliver immunosuppressive genes o To investigate altering cytokine gene expression in order to suppress the inflammatory process o To develop vectors that are targeted to the pancreatic beta-cell to deliver genes that interfere with its immunodestruction o To investigate the expression of protective genes in beta-cells to prevent immunodestruction o To explore the use of altered expression of other genes in the glucose metabolic pathway for their therapeutic potential to complement the effects of insulin o To investigate expressing genes involved in mouse and human beta-cell differentiation to determine their role in transdifferentiation of cell types such as hepatocytes and pancreatic duct cells o To develop strategies to prevent and/or delay the onset of complications such as the targeted expression of growth factors o To investigate the expression of genes that may regulate wound healing o To investigate the expression of genes to prevent and/or delay the onset of peripheral vascular diseases o To develop gene therapy approaches to alter the expression of the receptors for Advanced Glycated Endproducts o To develop gene therapy methodologies to effectively treat various complications and validate them in relevant animal models o To develop carefully designed pilot clinical gene therapy studies for diabetic complications. 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. 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. LETTER OF INTENT Prospective applicants are asked to submit, by October 16, 2000, 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. 653 MSC 5452 Bethesda, MD 20892-5452 (for express/courier service: Bethesda, MD 20817) Telephone: (301) 594-8885 FAX: (301) 480-3505 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms 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. 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 Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $100,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $100,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. The Letter of Intent should include information on establishing a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations. o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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. 653 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, NIAID, and NHLBI. Incomplete applications will be returned to the applicant. 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, the National Allergy and Infectious Diseases Advisory Council and the National Heart, Lung, and Blood 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: October 16, 2000 Application Receipt Date: November 16, 2000 Peer Review Date: February/March 2001 Council Review: May 30-31, 2001 Earliest Anticipated Start Date: July 1, 2001 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit as determined by peer review; o Innovation; o First time NIH awardee; 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: Catherine_McKeon@nih.gov Elaine Collier, MD Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Drive, Room 5135 MSC 7640 Bethesda, MD 20892-7640 Telephone: (301) 496-7104 FAX: (301) 402-2571 E-mail: ec5x@nih.gov Sonia I. Skarlatos, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10186, MSC7940 Bethesda, Maryland 20892-7940 Telephone: (301) 435-0545 FAX: (301) 480-2849 E-mail: skarlats@nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Denise Payne Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 626 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8845 FAX: (301) 480-3504 E-mail: PayneD@extra.niddk.nih.gov Mary Ledford Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6700-B Rockledge Dr., Room 2249, MSC 7614 Bethesda, MD 20892-7614 Telephone: (301) 402-6446 FAX: (301) 493-0597 E-mail: ml28g@nih.gov Jane Davis Division of Extramural Activities National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7174, MSC 7926 Bethesda, Maryland 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 E-mail: davisj@nhlbi.nih.gov AUTHORITY AND REGULATIONS These programs are described in the Catalog of Federal Domestic Assistance No. 93.847, 93.855, and 93.837. 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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