STEM CELL TRANSPLANTATION TO ESTABLISH ALLOCHIMERISM Release Date: September 4, 1998 P.T. RFA: HL-98-022 National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: October 26, 1998 Application Receipt Date: November 24, 1998 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The Cellular Hematology Scientific Research Group, Division of Blood Diseases and Resources, NHLBI, and the Hematology Program, Division of Kidney, Urologic, and Hematologic Diseases, NIDDK, announce the availability of a Request for Applications (RFA) on the above subject. The objective of this initiative is to develop improved and novel preparative regimens that will permit incompatible hematopoietic stem cell transplantation in immunized recipients with hemoglobinopathies. The possibility of successful stem cell transplantation for hemoglobinopathies being performed where complete myeloablation is not desirable and partial replacement of defective marrow may be sufficient for clinical benefit needs to be explored. The overall goal of the initiative is to focus on approaches to enable successful stem transplantation for hemoglobinopathies and minimize recipient morbidity and mortality. It is important that the approaches proposed include the potential to evolve into human clinical studies. Such studies will undoubtedly improve the morbidity and mortality associated with marrow and stem cell transplantation for hemoglobinopathies. 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 initiative is related to the priority areas of maternal and infant health and cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State 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. Domestic applications may include foreign components. FOREIGN INSTITUTIONS: Awards under this announcement may be made to foreign institutions provided the application (1) is of high scientific merit and (2) offers a special opportunity for furthering research programs through the use of unusual talents, resources, populations, or conditions in other countries which are not readily available in the United States or which augment existing U.S. resources. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. Newly independent investigators who may wish to consult with a program representative (see INQUIRIES section) are encouraged to apply. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 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. For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of ten modules ($250,000 direct costs) per year may be requested. Any necessary escalation must be included within the number of modules being requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support and Checklist information will be requested by NHLBI or NIDDK staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. 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 four years of support may be requested. 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 and NIDDK. It is anticipated that support for the present program will begin August 1999. Administrative adjustments in project period or amount of support may be required at the time of the award. 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. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded in connection with this RFA. FUNDS AVAILABLE It is anticipated that for fiscal year 1999, $2 million total costs will be available for the first year of support for this initiative by the NHLBI. Award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that approximately five to six new grants will be awarded under this program. The NIDDK plans to allocate an additional $1 million in total costs for the first year of support and plans to fund up to three applications. Applicants may request up to four years of support. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Facilities and administrative costs will be awarded based on the negotiated rates. If collaborative arrangements involve subcontracts with other institutions, Ms. Jane R. Davis of the NHLBI Grants Operations Branch (telephone: (301) 435-0166) should be consulted regarding procedures to be followed. RESEARCH OBJECTIVES Background The objective of this initiative is to develop improved and novel preparative regimens that will permit incompatible hematopoietic stem cell transplantation in immunized recipients with hemoglobinopathies. The possibility of successful stem cell transplantation for hemoglobinopathies being performed where complete myeloablation is not desirable and partial replacement of defective marrow may be sufficient for clinical benefit needs to be explored. The overall goal of the initiative is to focus on approaches to enable successful stem cell transplantation for hemoglobinopathies and minimize recipient morbidity and mortality. It is important that the approaches proposed include the potential to evolve into human clinical studies. Such studies will undoubtedly improve the morbidity and mortality associated with marrow and stem cell transplantation for hemoglobinopathies. Sickle cell disease is a complex syndrome with multiple organ system disturbances brought about through the interplay of genetic, humoral, vascular, and environmental factors. The clinical course can be one of abrupt and insidious exacerbations and remissions, often migratory and repetitive. These events may result in impairment of function, permanently damaged organs, and ultimately death. Although there is wide variability in the clinical expression of sickle cell disease, ranging from mild to very severe, this complex set of clinical manifestations is experienced by most patients. Recent progress has now enabled clinicians to offer patients with sickle cell disease treatment that extends beyond traditional supportive care (1). However, these therapies are not free from risk and are not appropriate for every patient. Transfusions carry risks of alloimmunization, iron overload, and transfusion transmitted infections. In the absence of effective iron chelation therapy, iron overload leads to numerous complications including delayed or absent sexual development, diabetes mellitus, cirrhosis, cardiac arrhythmias, and congestive heart failure. Recently, histocompatible hematopoietic stem cell transplantation for sickle cell disease was demonstrated to have curative potential, a feature which distinguishes it from ameliorative therapies such as hydroxyurea and chronic red cell blood transfusions (2,3). Thus, HLA-matched stem cell transplantation for sickle cell disease in Europe and the U.S. has clearly benefitted a selected group of patients experiencing recurrent neurological, pulmonary, and vaso-occlusive events. However, the morbidity and mortality associated with transplantation has led most patients with hemoglobinopathies (see Cooley's anemia below) and their physicians in the United States to pursue alternative therapies which only ameliorate the disease. An additional confounding factor in selecting patients for marrow transplantation is that there are no reliable predictors to identify the patients who are at the greatest risk of progressing to significant morbidity and mortality. Cooley's anemia, another genetic blood disease, results in an inadequate production of hemoglobin, the essential oxygen-carrying substance in blood. This causes severe anemia that begins shortly after birth. As a group, thalassemic disorders comprise one of the most common single-gene genetic diseases worldwide. In the United States, thalassemia mainly affects specific ethnic groups, including people of Mediterranean, Middle Eastern, African, Southeast Asian, Chinese, and Asiatic Indian origin. Individuals affected with Cooley's anemia require frequent and lifelong blood transfusions to sustain life. Because there are no natural means for the body to eliminate iron, the iron contained in the transfused red blood cells builds up over many years and eventually becomes toxic to tissues and organ systems. This excess iron must be removed from Cooley's anemia patients or they may not survive beyond the second decade of life. To accomplish this, patients must use the iron-binding or chelating drug, deferoxamine, that is administered for about ten hours every day by pumping it through a needle inserted either under the skin or intravenously. The addition of chelation therapy with deferoxamine to the treatment of Cooley's anemia has dramatically improved the outcome for affected patients. With regular chelation therapy, the accumulation of excessive iron can be prevented. Studies have demonstrated that well chelated patients have normal or only modest increases in liver iron, improved growth, normal sexual development, and most importantly, a markedly reduced chance of developing iron induced heart disease. Therefore, well chelated patients have a greater chance of achieving long-term survival. However, compliance with this demanding treatment regimen remains a difficult challenge for many patients. The majority of patients with Cooley's anemia report a negative impact of this onerous regimen on their quality of life. Thus, some patients are unable to continue this treatment during late childhood and adolescence. In the United States, the inability of patients with Cooley's anemia to comply with prolonged subcutaneous or intravenous infusions represents the primary obstacle to the reduction of body iron and is the reason some patients still die of the complication of iron overload. Bone marrow transplantation is used frequently in other countries as an alternative approach to the treatment of patients with sickle cell disease and Cooley's anemia (4,5). For patients undergoing transplantation with bone marrow from a matched sibling, the probability of thalassemia-free survival is reported to be between 75% and 95%, depending upon their disease status at the time of transplantation. The outcome depends on several factors including the severity of liver damage, the degree of iron overload, and the transplant center. Due to the morbidity and mortality associated with bone marrow transplantation, few hemoglobinopathy patients have received this treatment in the United States. Thus, the development of novel nontoxic or minimal myeloablative conditioning with the aim of creating stable donor-host mixed chimerism and decreasing the toxicities associated with transplantation is central to this RFA. Murine studies indicate significant levels of engraftment following 100 cGy whole body irradiation. This level of myeloablation is associated with minimal myelotoxicity (6). Studies by Ildstad and colleagues (7) indicate that relatively nontoxic treatment can lead to high rates of chimerism in mismatched murine allogeneic models. These data can potentially be extrapolated to humans. Recent data, in older patients with chronic lymphocytic leukemia (CLL), suggest that stable allochimerism can be created with relatively nontoxic preparative regimens for treatment of hemoglobinopathies (8). Walters and colleagues reported sickle cell disease patients with stable mixed chimerism for two years who are free of symptoms (9). For hemoglobinopathy patients, split chimerism may produce stabilization/cure without some of the toxicities associated with complete donor lymphohematopoietic engraftment. Since most patients with hemoglobinopathies have normal immune systems and would have been transfused, preparative regimens that will permit histoincompatible hematopoietic stem cell engraftment in immunized hosts should be developed. More information is needed on different "minimal" ablative regimens for obtaining split chimerism, on approaches for maximizing tolerance induction, on post-transplant therapy to minimize the risk of acute and chronic graft-versus-host disease and on stem cell and facilitator cell doses and roles in such engraftment. In addition, further information is needed on host treatment which might modify the degree of chimerism. The results of these studies could significantly impact the treatment of hemoglobinopathies and have broader implications for the field of transplantation and treatment of autoimmune diseases such as lupus, scleroderma, rheumatoid arthritis, diabetes and multiple sclerosis. The above examples of research approaches are not meant to be all inclusive or restrictive. Prospective applicants are encouraged to develop their own ideas of research on which to focus to address the goals of the RFA. Proposals which include basic and preclinical models that will evolve into future human clinical studies would be responsive to this RFA. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI and the NIDDK will sponsor annual meetings to encourage the exchange of information among investigators who participate in this program. In the preparation of the budget for the grant application, applicants should REQUEST ADDITIONAL TRAVEL FUNDS for one meeting each year to be held in Bethesda, Maryland. Applicants should also include a statement in the applications indicating their willingness to participate in such 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 research. This 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) which have been in effect since 1990. The policy contains some new 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 in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the 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 specific 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: https://grants.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit, by October 26, 1998, 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 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: js110j@nih.gov APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (rev. 5/95). Application kits 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. Use the conventional format for research grant applications and ensure that the points identified in the section on REVIEW CONSIDERATIONS are fulfilled. BUDGET INSTRUCTIONS Sample budgets and justification page will be provided upon request or following the submission of a letter of intent. 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: o FACE PAGE As a reminder, Item 7 should be completed to indicate Modular Direct Costs requested and Item 8 should reflect Total Costs (Modular Direct plus F&A costs). o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 5/95). It is not required nor will it be accepted at the time of application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev. 5/95). Only the requested total direct costs line for each year must be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of ten modules ($250,000 direct costs) per year may be requested and each applicant may request up to four years of support for this RFA. Direct cost budgets will remain constant throughout the life of the project (i.e., the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the Entire Proposed Project Period should be shown in the box provided. o BUDGET JUSTIFICATION Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried)and provide a narrative justification for each person based on his/her role on the project. Identify all consultants by name and organizational affiliation and describe the services to be performed. Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. No specific costs for items or categories should be shown. CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and indirect) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall $175,000 direct costs requested in the first year". A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility for an award, the applicant will be requested to identify actual direct and facilities and administrative costs for all years of the consortium. Note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. If clarification of the policy is needed, contact Ms. Jane R. Davis (under INQUIRIES). BIOGRAPHICAL SKETCH - A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. - Complete the educational block at the top of the form page; - List current position(s) and those previous positions directly relevant to the application; - List selected peer-reviewed publications directly relevant to the proposed project, with full citation; - The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI staff if there is a possibility for an award. CHECKLIST - No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI or NIDDK staff if there is a possibility for an award. - 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. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. The RFA label available in the PHS 398 (rev. 5/95) 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. Send or deliver the completed application and three signed, exact photocopies of it to the following, making sure that the original application with the RFA label attached is on top: 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) Send an additional two copies of the application to the Dr. Scheirer at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Center for Scientific Review (CSR). Otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by November 24, 1998. If an application is received after that date, it will be returned to the applicant without review. The 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 already 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 NHLBI and NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant 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 by the NHLBI in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. 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 judging the likelihood that the proposed research will have a substantial impact on the pursuit of these goals and those of the RFA, the reviewers will address each of the listed criteria, and consider them in assigning the overall priority score, weighting them as they feel appropriate for each application. Please note that your grant application may not need to be strong in all categories to be judged likely to have a 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 the 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 proposed study 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 performed 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 applicant 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 The 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 in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. AWARD CRITERIA The anticipated date of award is August 1999. Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. 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. Designated funding levels are subject to change at any time prior to award, due to unforeseen budgetary, administrative and/or scientific developments. INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants should request a copy of the full RFA, which will include sample budget pages as previously stated. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Dr. Helena O. Mishoe Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10156 Bethesda, MD 20892-7950 Telephone: (301) 435-0050 FAX: (301) 480-0868 Email: hm31y@nih.gov Dr. David G. Badman Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-13C, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: badmand@extra.niddk.nih.gov Direct inquiries regarding fiscal matters to: Ms. Jane R. Davis Grants Management Office National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: jane_davis@nih.gov Ms. Aretina Perry-Jones Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN-38B, MSC 6600 Bethesda MD 20892-6600 Telephone: (301) 594-8862 Email: perrya@extra.niddk.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.839 and 93.848. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grant policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or to 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. References 1. Charache S; Terrin ML; Moore RD; Dover GJ; Barton FB; Eckert SV; McMahon RP; Bonds DR: Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia [see comments] N Engl J Med May 18;332(20):1317-22, 1995. 2. Olivieri NF, et al: Hydroxyurea in children with sickle cell disease: impact on splenic function and compliance with therapy. J Pediatr Hematol Oncol. Jan; 20(1): 26-31, 1998. 3. Rana S, Houston PE, Surana N, Shalaby-Rana EI, Castro OL: Discontinuation of long-term transfusion therapy in patients with sickle cell disease and stroke. J Pediatr Nov;131(5):757-760, 1997. 4. Vermylen C, et al: Bone marrow transplantation for sickle cell anemia. Curr Opin Hematol. Mar; 3(2): 163-166, 1996 Review. 5. Lucarelli G: Bone marrow transplantation for thalassemia. J Intern Med Suppl; 740:49-52, 1997. 6. Stewart FM, Zhong, S, Wuu J, Hsieh C, Nilsson SK, Quesenberry PJ: Lymphohematopoietic engraftment in minimally myeloablated hosts. Blood; May 15;91(10):3681-7, 1998. 7. Colson YL, Li H, Boggs SS, Patrene K, Johnson PC, Illdstad ST: Durable mixed allogeneic chimerism and tolerance by a non-lethal radiation-based cytoreductive approach. J Immuno157: 2820, 1996. 8. Montserrat E: New therapeutic issues in CLL. Hematol and Cell therapy 39: S45,1997. 9. Walters MC; Patience M; Leisenring W; Eckman JR; Scott JP; Mentzer WC; Davies SC; Ohene-Frempong K; Bernaudin F; Matthews DC; Storb R; Sullivan KM: Bone marrow transplantation for sickle cell disease [see comments] N Engl J Med Aug 8;335(6):369-76, 1996.
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