Full Text HD-94-010 GENE THERAPY FOR DISORDERS CAUSING MENTAL RETARDATION NIH GUIDE, Volume 22, Number 43, November 26, 1993 RFA: HD-94-010 P.T. 34 Keywords: Gene Therapy+ Mental Retardation Metabolic Diseases Genetics National Institute of Child Health and Human Development Letter of Intent Receipt Date: November 26, 1993 Application Receipt Date: March 25, 1994 PURPOSE The Mental Retardation and Developmental Disabilities Branch (MRDD), Center for Research for Mothers and Children (CRMC), National Institute of Child Health and Human Development (NICHD), invites program project grant applications to develop new technologies, or improve existing ones, for gene therapy targeted toward disorders causing mental retardation. For the purpose of this Request for Applications (RFA), the diseases of interest are restricted to genetic conditions in which mental retardation is the primary clinical manifestation. Genetic disorders causing mental retardation include defects of amino acid metabolism, urea cycle defects, organic acidemia, carbohydrate metabolism (e.g., galactosemia), peroxisomal disorders, trace metal defects, lysosomal storage diseases, and disorders of purine metabolism (e.g., Lesch-Nyhan syndrome). Whatever organs are necessary to target for gene transfer to correct or prevent mental retardation could be considered in response to this RFA. Four to five P01s may be funded under this grant solicitation. Assignment of grants to appropriate Institutes will be based on current National Institutes of Health (NIH) referral guidelines. 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 RFA, Gene Therapy for Disorders Causing Mental Retardation, is related to the priority area of chronic disabling conditions. 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 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, and units of State or local governments, and eligible agencies of the Federal government. Applicants may collaborate, through consultation or contractual arrangements, with foreign investigators. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the NIH program project grant mechanism (P01). The applications should be prepared in a manner consistent with the information presented in the publication P01 PROGRAM PROJECT GUIDELINES, DIVISION OF SCIENTIFIC REVIEW, NICHD, which is available from NICHD program staff listed under INQUIRIES. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for applications submitted in response to this RFA may not exceed five years. The anticipated date of award is September 30, 1994. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to the customary NIH peer review procedures. FUNDS AVAILABLE It is estimated that program project applications submitted in response to this RFA will compete for approximately $3 million in direct costs that will be made available for the first year of support. It is anticipated that four to five awards will be made. The number of awards depends on the overall scientific merit of the applications and the availability of funds in fiscal year 1994. RESEARCH OBJECTIVES The MRDD Branch supports research that relates to the biological, behavioral, and social processes that contribute to, or influence the development of, mental retardation and developmental disabilities. Prevention of MRDD and amelioration of the clinical manifestations of those afflicted constitute areas of special emphasis within the Branch. To accomplish its mission, the Branch uses the mechanisms of research grants, supports special core facilities in the Mental Retardation Research Centers, provides contract support for development of new research resources, and disseminates information to the scientific community and the public. Genetic disorders have become increasingly prominent in the etiology of mental retardation, particularly in severe cases, i.e., I.Q. <50. In a survey of 122 severely mentally retarded children in Sweden, 36 percent were found to have demonstrable chromosome abnormalities, and 5 percent were caused by mutant genes. In addition, 20 percent had multiple congenital anomaly syndromes, and 16 percent had perinatal or unidentified prenatal causes. Since a large proportion of the multiple congenital anomaly syndromes, especially those that affect the central nervous system, and some of the unidentified prenatal causes are genetically determined, it is likely that genetic causes accounted for more than 50 percent of the total. With aggressive use of antimicrobial agents to treat infectious diseases, widespread immunization programs to protect against bacterial and viral infectious agents, better nutrition, and surgical correction of congenital abnormalities, increasing numbers of mentally retarded children, including those with genetic defects, who otherwise would have succumbed, are able to survive and live longer. Significant progress has been made in several areas of research relevant to gene therapy. The concepts have evolved quite rapidly from in vitro cellular and molecular studies, preclinical studies on an expanding list of animal models for human genetic disorders, to actual clinical gene therapy involving human subjects. The number of cloned and characterized genes is increasing rapidly; we now have a better understanding of the nature of disease-producing mutations, and gene regulation; a much improved and growing list of gene delivery systems are available; and various methods can now be applied to develop animal models for genetic disorders. In addition, the limited number of approaches that are currently available to treat some genetic disorders, such as dietary restriction, and enzyme replacement, are not completely successful and require life-long treatment. This RFA solicits applications that will address methods to efficiently transfer foreign genes into human and other mammalian systems, including transfer of genetically modified cells to recipient tissues, organs, or animal models; develop methods for sustained survival, and controlled expression of transferred foreign genes in vivo by developing and using appropriate enhancers and other regulatory sequences; develop genetic animal models of human diseases by homologous recombination, gene knockout, and other methods; and initiate human clinical trials for conditions that cause mental retardation. Proposed projects should evaluate the efficacy, long-term effects, safety and, in human trials, neuropsychological outcomes. SPECIAL REQUIREMENTS Note concerning FDA regulation of human gene therapy and somatic cell therapy: Human gene therapy and somatic cell therapy involve the administration to patients of materials considered biological products, and thus subject to regulation by the Center for Biologics Evaluation and Research (CBER), FDA. Investigational new drug (IND) applications are filed concerning clinical use of such products. Investigators planning clinical studies in these areas or preclinical and animal studies in support of future applications should inform themselves concerning the types of preclinical studies that are appropriate for such biological products. CBER has prepared a document entitled "Points to Consider in Human Somatic Cell Therapy and Gene Therapy (1991)," which provides guidance in this area. Other relevant Points to Consider documents should also be consulted. These may include: Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology (1985) Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals (1987) Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use (1987) Points to Consider in the Collection, Processing, and Testing of Ex-Vivo-Activated Mononuclear Leukocytes for Administration to Humans (1989) Copies of Points to Consider documents are available from: Division of Congressional and Public Affairs Center for Biologics Evaluation and Research HFM-12 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 CBER staff are also available for questions about which types of therapies are covered, for consultation, or for arrangement of pre-IND meetings at (301) 594-5114. Note Concerning Institutions with NIH-funded GCRC 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. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy requires applicants for NIH grants that have a clinical research component to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear and compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 (rev. 9/91) in Sections 1-4 of the Research Plan and summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). In that case, the rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to, clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by the applicants. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and reflected in assigning the priority score to the application. In addition, NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit, by November 26, 1993, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, titles of the component subprojects and the principal investigator, core facilities, when applicable, and the director of each core, names 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 subsequent applications, the information that it contains allows NICHD staff to estimate the potential review workload and to avoid possible conflict of interest in the review. The letter of intent is to be sent to Dr. Felix F. de la Cruz at the address listed under INQUIRIES. APPLICATION PROCEDURES The applicant is to submit the application using PHS 398 (rev. 9/91). Application kits containing this form and the necessary instructions are available in most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. The RFA label available in the PHS 398 (rev. 9/91) 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, including the Checklist, and three signed, photocopies in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Susan C. Streufert, Ph.D. Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E-03 Bethesda, MD 20892 Applications must be received by March 25, 1994. 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. The DRG 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 DRG and responsiveness to the RFA by the NICHD staff. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NICHD staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Under certain circumstances, applications may be triaged by a peer review group on the basis of relative competitiveness. If so, the NIH will withdraw from further competition those applications judged to be non-competitive for an award and notify the applicant Principal Investigator and institutional official. Applications judged to be competitive will undergo further scientific merit review. Applications that are complete and responsive will be evaluated for scientific and technical merit by a review panel convened solely for this purpose by the Division of Scientific Review, NICHD. The second level of review will be provided by the National Advisory Child Health and Human Development Council. Review Criteria Review criteria for RFAs are generally the same as those for unsolicited research grant applications. o scientific, technical, or medical significance of the application; o appropriateness and adequacy of the experimental approaches proposed to carry out the research; o coordination, interrelationship, cohesiveness, and synergism among the individual research projects and core components; relationship of the program objectives to the common theme; the advantages of pursuing the proposed research as a P01 rather than through individual research grants; o qualifications and research experience of the Principal Investigator for the entire program, and the principal investigators for the component projects; o participation of a suitable number of responsible, experienced investigators; o the specific scientific objectives of each project that will benefit from, depend upon, or contribute to collaborative interactions with the other component projects within the P01 (i.e., objectives that can be accomplished with greater effectiveness, and/or economy of effort, etc.); o an appropriate organizational and administrative structure for effective attainment of program objectives; o arrangements for internal quality control of ongoing research, the allocation of funds, day-to-day management, contractual agreements, and internal communication and cooperation among program investigators; o availability and quality of resources and research environment; o appropriateness of the proposed budget and duration in relation to the proposed research; o when applicable, quality of proposed core facilities; o adequacy of plans for the protection of human subjects; o adequacy of plans to protect against or minimize adverse effects on animals; and o inclusion of women and minority subjects in research. AWARD CRITERIA In addition to the scientific and technical merit of the application, other factors will be considered in making the awards. Among these are: o relevance to mental retardation; o access to unique populations; and o institutional commitment and support. The anticipated date of award is September 30, 1994. INQUIRIES Written and telephone inquiries regarding this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants are welcome. Requests for the program project guidelines, the letter of intent, and inquiries regarding programmatic and scientific issues may be directed to: Felix F. de la Cruz, M.D., M.P.H. Mental Retardation Developmental Disabilities Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B-09 Bethesda, MD 20892 Telephone: (301) 496-1383 Fiscal and administrative inquiries may be directed to: Mr. E. Douglas Shawver Office of Grants and Contracts National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A-17 Bethesda, MD 20892 Telephone: (301) 496-1303 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.865, Research for Mothers and Children. 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. .
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