Full Text HL-93-014 IN UTERO STEM CELL TRANSPLANTATION FOR GENETIC DISEASES NIH Guide, Volume 22, Number 14, April 9, 1993 RFA: HL-93-014 P.T. 34 Keywords: Blood Diseases Transplantation of Organs Disease Model National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: October 1, 1993 Application Receipt Date: November 17, 1993 PURPOSE The Cellular Hematology Branch, Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute (NHLBI), invites applications for studies that may contribute to the development of methodologies to perform in utero hematopoietic stem cell transplants to cure genetic blood diseases that can both be diagnosed in utero and are curable by postnatal marrow transplantation. The specific focus will be on animal models, but human studies will also be considered. 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), In Utero Stem Cell Transplantation for Genetic Diseases, is related to the priority areas of Cooley's anemia, sickle cell anemia, other genetic blood diseases, and hematopoietic stem cell transplantation. 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, DC 20402-9325 (telephone 202-782-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Awards in response to this RFA will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research grant (R01) and FIRST (R29) awards and is a one-time solicitation. Applicants, who will plan and execute their own research programs, are requested to furnish their own estimates of the time required to achieve the objectives of the proposed research project. Up to five years of support may be requested. Applicants for FIRST awards must request five years of support. At the end of the official award period, renewal applications may be submitted for peer review and competition for support through the regular grant program of the NHLBI. It is anticipated that support for the present program will begin in July 1994. Administrative adjustments in project period and/or amount of support may be required at the time of the award. All current policies and requirements that govern the research grant programs of the National Institutes of Health will apply to grants awarded in connection with this RFA. Since a variety of approaches would represent valid responses to this announcement, it is anticipated that there will be a range of costs among individual grants awarded. FUNDS AVAILABLE Although the financial plans for fiscal year 1994 include $1.5 million for this program, award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that about six new grants will be awarded under this program. The specific amount to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. If collaborative arrangements involve sub-contracts with other institutions, the NHLBI Grants Operations Branch (telephone 301-594-7436) should be consulted regarding procedures to be followed. RESEARCH OBJECTIVES In the past twenty years, allogeneic bone marrow transplantation increasingly has become used as a cure for a variety of genetic defects of the hematopoietic and immune systems and for lysosomal storage diseases. Genetic diseases that have been successfully cured by bone marrow transplantation include Cooley's anemia, sickle cell anemia, Fanconi anemia, Blackfan-Diamond anemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, infantile agranulocytosis, Chediak-Higashi disease, chronic mucocutaneous candidiasis, mucopolysaccharidosis, cartilage-hair hypoplasia, Gaucher's and other storage diseases. Some of these diseases, such as Cooley's anemia (beta-thalassemia) and sickle cell anemia, are major worldwide public health problems. Others are devastating orphan diseases that are extremely costly to treat. Genetic diseases that cause death in utero, such as homozygous alpha-thalassemia, may also possibly be cured by in utero stem cell transplantation. Collectively, these diseases occur in tens-of-thousands of births per year. However, conventional bone marrow transplantation has several drawbacks: (1) only about 35 percent of transplant candidates will have a suitably matched marrow donor; (2) the long-term effects of the preparative regimen of lethal doses of irradiation and/or cytotoxic drugs are not known; (3) post-transplant complications such as infection and graft-versus-host disease are significant and contribute to the morbidity and mortality of the procedure; (4) for some diseases, the disease process has caused irreversible damage prior to the transplant; and (5) the significant cost of the procedure which could be as much as $250,000, not including the possible long-term care for chronic graft-versus-host disease. In the sheep and monkey animal models, recent progress seems to indicate that donor fetal liver hematopoietic stem cells can be successfully transplanted into an unrelated pre-immune recipient fetus. After birth, the chimeric animals still appear healthy and normal up to five years post-transplant. This procedure has been performed without the need for tissue matching, without marrow ablation, without immunosuppressive drugs, and without the development of graft-versus-host disease. This suggests that the fetus is both an ideal recipient and donor of hematopoietic stem cells, as has recently been demonstrated by the long-term engraftment and expression of human stem cells in preimmune sheep fetuses. In a number of diseases (e.g., storage diseases), an early expression of donor cells activity (i.e., soon after transplant and before birth) is a critical requirement since even at birth significant clinical disease exists. In diseases such as Cooley's anemia and other hemoglobinopathies, a higher level of donor cell engraftment is needed to be of therapeutic benefit. In this regard, recent findings of improved donor hematopoietic stem cell engraftment as the result of homing receptor manipulations by growth factors are promising. The technical and quality control issues that are involved when fetal donor stem cells are used may limit the applicability of this source of stem cells. Although in animal studies and in limited clinical studies, T-depleted adult stem cells have failed to engraft adequately in utero. The significant progress in stem cell purification and characterization provides for new sources of donor stem cells. Moreover, the possibility of employing in vitro expanded fetal or adult stem cells for use in in utero transplants has not been explored. The possibility now exists for correcting genetic diseases in utero, without the significant problems that were described above for bone marrow transplantation. Therefore, this initiative is for the development of methodologies to perform in to perform in to ppero hematopoietic stem cell transplants to cure genetic diseases that can be diagnosed in utero and that are curable by postnatal marrow transplantation. Examples of Areas of Interest The following are only examples and prospective applicants are urged to use their own ideas as to the area of research on which to focus. The major areas that need further investigation before the procedure can be applied in clinical practice include, among others: (a) improved donor cell engraftment; (b) en oy expresssf donor cell activity; (c) the use of alternate sources of donor stem cells, such as fetal liver, adult peripheral blood, adult bone marrow, and hematopoietic stem cells that have been expanded in culture; and (d) quality control issues regarding the collection, processing, storage and use of donor hematopoietic stem cells. Disciplines and Expertise Among the disciplines and expertise that may be appropriate for this program are hematology, immunology, cell biology, medicine, and neonatology.ith no exclusions from the base for training-related expenses. RESEARCH OBJECTIVES The Minority Institutional Research Training Program is designed to offer research training grant awards in cardiovascular, pulmonary, and hematologic research to minority schools to enable qualified graduate students, health professional students, and postdoctoral students to participate in research programs. It is expected to attract students in the developmental stages, increase awareness of these diseases, and to acquaint them with career opportunities in research. The Minority Institutional Research Training Program is intended to: o Train graduate students, health professional students, and postdoctoral students at minority schools that have the potential to develop a meritorious program in cardiovascular, pulmonary, or hematologic research for research careers in areas relevant to these diseases. o Stimulate cardiovascular, pulmonary, and hematologic diseases and hematologic resources research, prevention, control, and education by offering minority school graduate students, health professional students, and postdoctoral students the opportunity to enhance their research capabilities in these areas. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91). Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 435-0714. The title and number of the RFA must be typed in section 2a on the face page of the application. The completed original application and three legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Two additional copies of the application must be sent to: Scientific Review Administrator Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 550 Bethesda, MD 20892 Applications must be received by November 17, 1993. REVIEW PROCEDURES All applications responding to this announcement will be reviewed for scientific and technical merit by the Research Training Review Committee of the Division of Extramural Affairs, NHLBI, followed by a second level review by the National Heart, Lung, and Blood Advisory Council. The factors to be considered in the evaluation of the proposed training program are: o Adequacy of faculty, facilities, and resources for the proposed research training, both at the minority institution and the research center; o Adequacy of the cooperative arrangements between the minority institution and the research program; o Commitment of the relevant faculty and the two institutions to the goals of the training program; o Procedures for evaluation of the impact of the program on the trainees involved. AWARD CRITERIA Applications will compete for available funds with other approved applications assigned to the National Heart, Lung, and Blood Institute. The following will be considered in making funding decisions: o Scientific and technical merit of the application as determined by peer review o Availability of funds o Program balance among the research areas of the announcement INQUIRIES Written and telephone inquires are encouraged. Guidelines for this program may be obtained from any of the following: John Fakunding, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Federal Building, Room 3C04 Bethesda, MD 20892 Telephone: (301) 496-1724 Fann Harding, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Federal Building, Room 5A08 Bethesda, MD 20892 Telephone: (301) 496-1817 Mary Reilly, M.S. Division of Lung Diseases National Heart, Lung, and Blood Institute Westwood Building, Room 640A Bethesda, MD 20892 Telephone: (301) 594-7466 For fiscal and administrative matters, contact: Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A15C Bethesda, MD 20892 Telephone: (301) 594-7434 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.837, 93.838, and 93.839. Awards will be made under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grants policies and Federal Regulations at 42 CFR Part 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. .
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