Full Text HL-96-019 GENE TRANSFER PRINCIPLES FOR HEART, LUNG, AND BLOOD DISEASES NIH GUIDE, Volume 25, Number 31, September 20, 1996 RFA: HL-96-019 P.T. Keywords: National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: January 10, 1997 Application Receipt Date: February 13, 1997 PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites Program Project grant applications for support of research efforts to advance gene transfer technology and its potential application to cardiovascular, pulmonary, and hematologic diseases. The overall objective of this program is to foster research that will provide the basic science foundation necessary for gene transfer technology and its application to somatic gene transfer by:(1)promoting the alliance of a critical mass of talented and dedicated investigators with expertise in the diverse areas essential for successful implementation of this research program; (2)providing the infrastructure needed to establish the collaboration of experts in a wide-ranging number of scientific areas; and (3)funding innovative pilot and feasibility studies to attract new and established investigators into the field of gene transfer for cardiovascular, pulmonary, and hematologic diseases. 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 request for applications (RFA), "Fundamental Biological Principles for Gene transfer for Cardiovascular, Pulmonary, and Hematologic Diseases", is related to the priority area of Heart Disease and Stroke, Diabetes and Chronic Disabling Diseases, and Maternal and Infant Health. Methodologies and biotechnological advances resulting from these studies may also be applicable to the priority areas of Cancer, and Food and Drug Safety. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No.017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, D.C. 20402-9325 (telephone 202-783-3283). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or 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. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Awards under this announcement will not be made to foreign institutions. MECHANISM OF SUPPORT This RFA will use the NIH Program Project grant (P01) mechanism of support (containing research projects and the requisite shared infrastructural resources (cores) as subcomponents under the aegis of the parent grant). A Program Project grant is for the support of a broadly-based multidisciplinary or multifaceted research program that has a specific major objective or central theme. The award may support research components and core functions. Collectively, these components should demonstrate essential elements of unity and interdependence and result in a greater contribution to program goals than if each activity were pursued individually. Applications must be prepared and awards will be made according to NHLBI Program Project policies. NHLBI Guidelines for the preparation of the Program Project Grant applications may be obtained from Dr. C. James Scheirer at the address listed under LETTER OF INTENT. Applicants are expected to furnish their own estimates of time required to achieve the objectives of the proposed research project. Up to 5 years of support may be requested. 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. It is anticipated that support for this program will begin in September 1997. Administrative adjustments in project period and/or amount may be required at the time of the award. FUNDS AVAILABLE It is anticipated that for fiscal year 1997, approximately $5,130,000 total costs will be available for the first year of support for this initiative. Applicants may request up to $1,140,000 direct costs, not including indirect costs for collaborating institutions, in the first year with a maximum increase of no more than 4 percent in each additional year requested. Award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that three program project grants will be awarded under this program. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Pilot and feasibility studies may be submitted to pursue promising but untested methodologies or highly novel research. Funding for such projects is included in the $1,140,000 direct cost cap. Each pilot and feasibility project may request up to $60,000 in total costs per year for a maximum of two years. New projects, subjected to the same dollar and time limits, may be proposed to replace those that terminate. At any one time, a maximum of 3 pilot and feasibility projects will be allowed per program project research grant. The mechanism for selecting and reviewing initial and subsequent pilot/feasibility projects during the 5 year tenure of this program is detailed in the special guidelines governing this program, available from the program administrators listed at the end of this announcement. Equipment is included in the budget limitation. However, requests for special equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires strong justification. Final decisions will depend on the nature of the justification and the availability of funds. CONSORTIUM ARRANGEMENTS If a grant application includes research activities that involve institutions other than the grantee institution, the program is considered a consortium effort. Such activities may be included in a Program Project grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. In addition, NHLBI requires that at least half of both the subprojects and cores submitted and funded be in the applicant institution. The published policy governing consortia is available in the business offices of institutions that are eligible for Federal grants-in-aid. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, contact William Darby, (301)435- 0177. Applicants for Program Project grants should clearly describe the interactions of the participants and the integration of the consortium project(s) with those of the parent institution, because synergism and cohesiveness can be diminished when projects are located outside the group at the parent institution. Indirect costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. INTER- AND INTRA-INSTITUTIONAL COLLABORATIONS A key ingredient for the success of this program is the multidisciplinary collaboration of investigators skilled in pursuing basic science principles in areas such as gene expression with researchers who are skilled in the application of such principles to gene transfer for cardiovascular, pulmonary and hematologic diseases. Hence, one of the objectives of this program is to foster the alliance of a critical mass of talented and dedicated investigators with expertise in the diverse areas essential for successful implementation of this research program. This intensive, multi-disciplinary enterprise will require substantial interaction and coordination among individuals skilled in molecular biology, virology, developmental biology, cellular biology, bioengineering, pathology, genetics, biochemistry, physiology and other disciplines dealing with biologic mechanisms and health and diseases. Program Project guidelines require that at least half of both the subprojects and cores submitted and funded be in the applicant institution. INFRASTRUCTURAL RESOURCES Another important objective of this initiative is to provide the infrastructure needed to establish the collaboration of experts in a wide-ranging number of scientific areas. In order to provide the appropriate infrastructure, funds may be utilized to support core resources as shared facilities. These "shared" resources form the structural foundation for the areas of scientific need and are an important goal of this program. Rather than being purely service oriented cores for performance of routine functions, there may be a need for some of these cores to be involved in technological developments, such as in the area of vectors. These "shared" infrastructural resources must be flexible enough to meet the needs of the constantly evolving science. As such, the investigators will be required to provide yearly progress reports delineating the functions of these cores for the previous and future project periods to assure that the cores are meeting the scientific and technical needs requisite for advancing gene therapy. PILOT AND FEASIBILITY STUDIES An important goal of this program is to attract new and established investigators into the field of gene therapy by providing access to critical technologies (in the form of shared resources described above) and funds to pursue innovative pilot/feasibility studies. Pilot and feasibility studies, when combined with appropriate core support, will provide established investigators who have not previously worked in gene transfer and new young investigators with state-of-the-art core technologies to be competitive in the field. In addition, pilot and feasibility studies will allow investigators to pursue promising but untested methodologies or highly novel, research avenues that may offer significant results and insight. However, funds for these pilot/feasibility studies are not intended to support or supplement ongoing funded research of an investigator. It is anticipated that by providing preliminary results and establishing feasibility data, these pilot studies will lead to new research proposals in the area of gene transfer as it will relate to prevention and treatment of cardiovascular, pulmonary and hematologic diseases. Applicants are requested to propose a Pilot and Feasibility Committee that will be responsible for developing and selecting those projects most likely to aid progress in achieving successful gene transfer. Each pilot and feasibility project may request up to $60,000 in total costs per year for a maximum of two years. New projects, subjected to the same dollar and time limits, may be proposed to replace those that terminate. At any one time, a maximum of 3 pilot and feasibility projects will be allowed per program project research grant. RESEARCH OBJECTIVES Background The introduction of genetic material into human cells with successful expression of the inserted gene is a historic technological advance. It allows the development of novel strategies for prevention control, and treatment of disease through the use of gene transfer. Conceptually, gene transfer can be used to correct or replace defective genes. Current approaches for gene transfer attempt to introduce genes in addition to the endogenous genome in an effort to restore or enhance normal cellular activities or to confer new cellular activities. This approach does not attempt to correct resident, nonfunctional mutant genes. The introduction of genetic material to prevent the expression of disease-causing genes is another gene transfer approach. At the present time, however, molecular genetic interventions for cardiovascular, pulmonary, and hematologic diseases face many difficult technical hurdles. Critical basic science issues must be addressed prior to transfer of this technology to the clinic. Expanded and new research efforts are necessary to develop the basic tasks involved in gene transfer, such as insuring regulated, stable and cell-specific expression of transferred genes in target cells, developing efficient gene transfer delivery systems, and producing animal models of cardiovascular, pulmonary, and hematologic disease in order to develop and test novel therapeutic approaches. In addition, gene transfer research affords the opportunity to further the understanding of the genetic components of single gene and multifactorial gene diseases. Hence, it is critical to facilitate research efforts that include molecular, cellular, genetic and preclinical studies to advance gene transfer technology and its application to a wide range of cardiovascular, pulmonary, and hematologic diseases. The potential of gene transfer to treat cardiovascular diseases is substantial. However, there are unique features of cardiovascular diseases that require special gene transfer approaches. For example, the focal nature of coronary artery disease and restenosis may require direct delivery of therapeutic genetic material to specific myocardial or vascular sites. Additional challenges encountered with cardiovascular cells include the non-dividing nature of some cell types, such as heart myocytes. Strategies for other cardiovascular diseases might include gene transfer to: treat myocardial ischemia by promoting collateral circulation; prevent vascular smooth muscle proliferation following angioplasty; and prevent cardiac transplantation rejection by altering the cell surface properties to deter an immune response. There are many opportunities for application of gene transfer techniques to prevention and treatment of pulmonary disorders. Although there have been several promising advances in the use of gene transfer approaches for cystic fibrosis, major barriers for this and other pulmonary diseases to further progress exist. Mechanisms that underlie the immune response to viral vectors need to be elucidated. The development and characterization of more efficient gene transfer delivery systems need to be established. The use of gene transfer to ameliorate or prevent inflammatory lung disorders such as ARDS and asthma is just beginning to be explored. Gene transfer to the pulmonary vasculature is also largely unexplored. The role of this approach to treating pulmonary thrombosis, pulmonary hypertension, or other conditions needs to be evaluated. Bronchopulmonary dysplasia, pulmonary fibrosis, and chronic obstructive pulmonary disease are other potential targets for the use of gene transfer. Many of the problems and needs relevant to gene transfer in the cardiovascular and pulmonary areas are generally applicable to hematologic genetic diseases, such as hemophilia, sickle cell disease, and thalassemia. Choice of the appropriate target cell ranges from important to critical for hematologic disorders. In the case of hemophilia, the normal site of production of factors VIII and IX is believed to be the liver; however, other target cells such as myoblasts and fibroblasts have been used in preliminary experiments. Also critical is access of the secreted gene product to the circulation. Studies of mechanisms of development and suppression of immunity to newly expressed gene products will also be an important issue. Thus, although much progress has been made, many basic issues crucial to clinical success remain. OBJECTIVES In order for key advances to take place in the needs outlined above, there are critical biological tasks that must be solved. Hence, the focus of this initiative will be on the fundamental questions related to applications of gene transfer technology for use in the cardiovascular, pulmonary, and hematologic systems. Clinical gene transfer trials are beyond the scope of this initiative. Research needs include: Gene Expression: It is important to understand the underlying mechanisms that determine how the transferred gene is expressed in sufficient amounts in the physiologically correct manner. Too much, too little, or inappropriately timed expression may be harmful. More information is also needed about secretion of expressed proteins into appropriate compartments or into the circulation. An understanding of cell specific and tissue specific gene expression, as it relates to gene transfer, is required. An understanding of the biological consequences of recombinant gene expression needs to be gained. Studies aimed at examining the effect of gene transfer on the normal biological function of the target cell, tissue and animal will be important. Gene Delivery and Transfer: Current techniques for inserting genes into target cells must be improved and new ones need to be developed to insure efficient gene transfer. Studies might involve viral, physical, chemical and fusion techniques to develop improved packaging and more effective gene delivery. Recent developments in controlled drug release technology, including the use of biodegradable polymers in the form of layers or microspheres and containing the desired gene, may be applicable to gene delivery. Relevant issues of immunity, safety, efficacy, and production require exploration. Research aimed at designing methods to insure cell-specific and stable long-term expression of transferred genes is essential. Development of techniques to target genes to specific chromosomal locations by homologous recombination need further exploration. Target Cells: There is a need to identify appropriate target cell populations for successful gene transfer treatment of cardiovascular, pulmonary, and hematologic diseases. Identification of stem cell populations, if appropriate, would be encouraged. In addition, methods for improved cell purification and routine isolation of highly purified cell populations, as have been developed for bone marrow cells, need to be established for other cells. Improved cell culture techniques for growth and maintenance of nontransformed cells are necessary and may involve the identification and use of cytokines and receptors that regulate cell growth. Efforts need to be directed toward isolating, purifying and maintaining cardiac and vascular myocytes, endothelial cells and cells in other organs that participate in cardiovascular, pulmonary, and hematologic disorders. Disease Pathophysiology: Basic studies in disease pathophysiology are critical to the eventual success of gene therapy. Such studies can lead to a better definition of the important target cell(s) and to more effective designs of therapeutic approaches. Cellular and Humoral Immunity: The role of cellular and humoral immunity in the gene transfer process needs clarification. Interventions to suppress the immune response are in need of exploration, as well as the development of novel vector systems that selectively minimize or repress the immune response of the host organism. Model Systems: Model systems (in vivo and in vitro) need to be developed and explored to assess the safety and efficacy of viral and nonviral vector systems. Animal models of human diseases allow researchers to design and evaluate gene transfer strategies that cannot be assessed in humans. Naturally occurring animal models that mimic human diseases occur occasionally. It is now possible, however, to use transgenic and gene targeting approaches to create and utilize animal models of human diseases. Hence, the generation and use of genetically altered animal models to develop and test gene transfer approaches needs to be encouraged. Clinical Applications: While funding for clinical gene therapy trials is beyond the scope of this initiative, the development of programs which will lead to cardiovascular, pulmonary, and hematologic gene transfer trials is encouraged. This might include the identification of candidate therapeutic genes; development of vector systems to optimize gene delivery and expression in target cells; and to test the safety and efficiency of gene expression in animal models. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request travel funds for a 1-day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. 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) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), that have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 reprinted in the NIH Guide to 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. LETTER OF INTENT Prospective applicants are asked to submit, by January 10, 1997, 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 staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be mailed, or faxed, to: Dr. C. James Scheirer Chief, Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301)435-0266 FAX: (301)480-3541 Email: James_Scheirer@NIH.GOV APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and 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, email: ASKNIH@odrockm1.od.nih.gov; and from the program staff listed under INQUIRIES. Special program project guidelines have been developed to meet the special features and needs of this RFA program and must be used in applying for these grants. These guidelines can be obtained from Dr. Sonia Skarlatos at the address listed under INQUIRIES. The RFA label found in the PHS 398 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 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application and three signed, photocopies, in one package 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) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the same address given above in the section on LETTER OF INTENT. Applications must be received by February 13, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness by the NHLBI. Incomplete applications will be returned to the applicant without further consideration. If NHLBI staff find that the application is not responsive to the RFA, it will be returned without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a triage 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 Heart, Lung, and Blood Advisory Council. The NIH will withdraw from further competition those applications judged to be noncompetitive for award and notify the applicant Principal Investigator and institutional official. The personnel category will be reviewed for appropriate staffing based on the requested percent effort and any changes requested in future years. The total budget request will be reviewed for consistency with the proposed methods and specific aims. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the recommended scope of the project. Other review criteria will include: o scientific, technical or medical significance and originality of proposed research o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research o appropriateness and design of the shared core facilities proposed to provide infrastructural support to the major scientific components of the gene therapy effort, including plans to monitor their performance and ability to meet changing scientific needs o adequacy and availability of the resources and facilities to support proposed clinical and basic research o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research originality of proposed research Investigator and staff, particularly, but not exclusively, in the area of the proposed research originality of proposed research o adequacy of internal and external procedures for monitoring and evaluating the proposed research and for providing on-going quality control and scientific review o scientific merit of any proposed pilot/feasibility studies and the quality of the internal and external review mechanism established by the parent institution to evaluate the scientific merit of the initial and subsequently selected pilot/feasibility projects, including development of a detailed plan for maintaining oversight and review of on-going pilot/feasibility studies and for providing written documentation of these actions, copies of which will be forwarded to the NHLBI Program Administrators o commitment of the grantee institution and any cooperating institution to the program, and the appropriateness of its resources and policies for the administration of a research program of the type proposed; and the appropriateness of the requested budget to the work proposed 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. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. Schedule Letter of Intent Receipt Date: January 10, 1997 Application Receipt Date: February 13, 1997 Initial Review: April/May 1997 Review by NHLBI Advisory Council: September 1997 Anticipated Award Date: September 30, 1997 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 and requests for the Program Project Guidelines to: Sonia Skarlatos, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10186 Bethesda, MD 20892-7956 Telephone: (301)435-0550 FAX: (301) 480-2848 Email: SKARLATS@GWGATE.NHLBI.NIH.GOV Susan Banks-Schlegel, Ph.D. Division of Lung Diseases National Heart, Lung and Blood Diseases 6701 Rockledge Drive, Suite 10220 Bethesda, MD 20892-7952 Telephone: (301)435-0202 FAX: (301)435-3557 Email: SCHLEGES@GWGATE.NHLBI.NIH.GOV Carol Letendre, Ph.D. Division of Blood Diseases and Resources National Heart, Lung and Blood Diseases 6701 Rockledge Drive, Suite 10162 Bethesda, MD 20892-7950 Telephone: (301) 435-0080 FAX: (301) 435-0867 Email: LETENDRC@GWGATE.NHLBI.NIH.GOV Direct inquiries regarding fiscal matters to: Mr. William Darby Grants Operations Branch National Heart, Lung, and Blood Institute Two Rockledge Center 6701 Rockledge Drive, Suite 7128 Bethesda, MD 20892-7128 Telephone: (301) 435-0177 FAX: (301) 480-3310 Email: William_Darby@NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. 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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