Full Text PA-97-092 GENE THERAPY IN AGING NIH GUIDE, Volume 26, Number 26, August 8, 1997 PA NUMBER: PA-97-092 P.T. Keywords: National Institute on Aging National Heart, Lung and Blood Institute National Institute on Deafness and Other Communication Disorders National Institute of Mental Health National Institute of Neurological Disorders and Stroke PURPOSE The objective of this initiative is to encourage research on strategies to prevent or delay adverse aging-related changes and diseases, including neurodegenerative disorders, using genetic and cellular engineering approaches. 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 PA, Gene Therapy in Aging, 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 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 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. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Support for this Program Announcement will be through the NIH research project grant (R01) and FIRST (R29) award. Applicants will be responsible for the planning, direction, and execution of the proposed project. The award of grants in response to this program announcement is also contingent upon the availability of funds. RESEARCH OBJECTIVES Background "The application of molecular genetics to human biology has had a profound effect on our ability to understand, diagnose, and treat a variety of diseases. The identification and cloning of a number of disease-related genes has provided us with a powerful set of tools for identifying susceptibility to disease and, more important, understanding the molecular pathophysiology of many disorders. More recently, the revolution in molecular medicine has also generated considerable enthusiasm for gene therapy." (Leiden, J. 1995. Gene Therapy - Promise, Pitfalls and Prognosis. New Eng. J. of Med.). Gene therapy approaches are currently being developed and tested for a wide variety of pathological conditions such as cystic fibrosis, cancer, AIDS, familial hypercholesterolemia, cancer, adenosine deaminase deficiency, Duchenne muscular dystrophy, etc. Although outright success has so far been limited for gene therapy approaches in humans, it is clear that this exciting technology has remarkable potential. This potential will increase as more genes are identified and cloned, and better vectors and delivery systems are developed. This emerging technology has been the focus of annual Keystone Symposia since 1993, as well as meetings at many other sites. An alternative but technologically related approach, especially in the near-term and with respect specifically to neurodegenerative disease, involves cell-engineering techniques. Examples of cellular engineering could involve the use of appropriate stem cell populations, or the implantation of genetically modified cells. Genetic and cellular engineering techniques could potentially provide a new approach to slow aging processes which may lead to pathology, as well as treat age-related disorders per se. The NIH is thus interested in supporting research to develop or facilitate the development of genetic and cellular engineering strategies to prevent or delay the losses of physiological function associated with aging. In particular, the NIA encourages experimental research which could contribute to therapies or preventive interventions based on altering the underlying aging processes that contribute to or cause age- related disorders. Identification of genetic factors controlling pathophysiologic aging processes may then contribute to development of more fundamental and definitive therapy and prevention of age- related diseases. Gene-based intervention techniques could allow experimental manipulations previously impossible in therapeutic aging studies. These include an increased range of gene products (e.g., intracellular proteins) whose levels can be directly and specifically manipulated, direct control over the level of a gene's expression at any point in the life span or at any phase of diurnal or other cycles, tissue-specific control of gene expression, and an expanded range and improved control of secretory products which could be directly manipulated. Gene-based intervention techniques could also be used to: 1) develop better animal models of human aging changes; 2) introduce markers to track cells transplanted to modify aging changes, and 3) screen potential non-genetic interventions against aging processes in genetically-engineered cells in vitro. The following references provide general background information in support of this initiative: 1. Leiden J. 1995. Gene therapy - Promise, pitfalls and prognosis. N. Eng. J. Med. 333: 871-872. 2. Blau HM, Springer ML. 1995. Gene therapy - A novel form of drug delivery. N. Eng. J. Med. 333: 1204-1207. 3. Evans CH, Robbins PD. 1995. Possible orthopedic applications of gene therapy. J. Bone Joint Surg. 77A: 1103-1114. 4. Smithies O, Malda N. 1995. Gene targeting approaches to complex genetic diseases: Atherosclerosis and essential hypertension. Proc. Natl. Acad. Sci. USA 92: 5266-5272. 5. Lindsay RM. 1995. Neuron saving schemes. Nature 373: 289-290. 6. Barinaga M. 1994. Neurotrophic factors enter the clinic. Science 264: 772-774. Scope This program announcement solicits grant applications for experimental studies to determine effects of genetic interventions on age-associated morbidity, age-related changes in physiologic function and/or life span, in either or both of two major categories: 1. Genetic or cellular engineering interventions initiated in young or middle-aged animals to alter fundamental processes whose functioning throughout the life span may affect rates of progression of degenerative aging changes, or age of onset of morbid conditions. 2. Genetic or cellular engineering interventions to reverse or prevent adverse aging changes or morbidity resulting from altered expression with age of particular genes, or from loss of functioning differentiated cells. In these studies, the use of experimental design and controls that maximize interpretability of results is encouraged. Examples include strategies to determine whether putative genetic effects may be related to alterations in caloric intake, which itself affects many aging processes, and sample sizes and compositions which allow determination of varying effects in different genders and strains, where appropriate. Where feasible, measurement of intervention effects by individuals blinded to the intervention status of the animal is also strongly encouraged. Interventions that are of particular interest include, but are not limited to: * Damage and repair of cell and tissue components (e.g., attenuation of oxidative damage to DNA, proteins and lipids), including in red blood cells. * Cell proliferation, cell death, and maintenance of cell function in specific tissues, including red blood cells. * Production of (and tissue responsiveness to) secretable products such as growth factors, hematopoietic factors, neurotrophic factors, hormones, neurotransmitters, or other extracellular factors. * Maintenance of immune function, prevention of autoimmunity, and wound healing. * Regulation of diurnal cycles, reproductive cycles, and other biological or sleep/wake rhythms. Genes of particular interest for genetic interventions include: * Genes for which comparative biologic or epidemiologic studies suggest relationships of DNA polymorphisms or mutations to aging rates, longevity, or age-related disease. * Genes whose expression is altered by long-term caloric restriction, and which may be causally related to the life span extension and retardation of aging processes induced by caloric restriction in several species. * Genes which are relevant to progeroid syndromes in which several age-related changes are accelerated, e.g. Werner's syndrome, Bloom's syndrome, Down's syndrome, and Cockayne's syndrome. * Genes responsible for recessive conditions which also contribute to accelerated age-related pathology when present in heterozygotes for these loci. * Genes whose role in neurodegeneration is under oxygen-dependent regulation, and which are stimulated by the pattern of hypotoxic insult produced by sleep apnea and other defects in ventilatory control. Interventions with particular relevance to neurodegenerative diseases include: * The delivery of genes or gene products to primate CNS or other appropriate animal model which may be therapeutic in neurodegenerative, neurogenetic and neurovascular diseases in aged brain and sensory organs. Delivery of gene products includes the use of genetically modified stem cells and other cell types. * Improvements in vectors to yield regulatable, sustained long-term expression of transgenes, such as those for neurotransmitter synthesizing enzymes and receptors, or neuroprotective, neurotrophic and neuronal guidance molecules. * The development of strategies to target transgenes to specific cell types within the CNS, to monitor and assess host responses (cytotoxicity) to the vector/gene constructs, and where necessary, to develop novel delivery systems to bypass the blood-brain barrier. This program announcement encourages studies using gene-based intervention techniques to develop better animal models of human aging changes. It also encourages in vitro studies to screen potential non-genetic interventions against aging processes in genetically-engineered cells. This announcement does not solicit research on vector development, but does encourage research on development of regulatable vectors to allow controlled expression of transgenes at desired phases of the life span, to restore cyclic patterns of gene expression which are altered with advancing age, or to solve problems peculiar to gene or cell delivery in older organisms. 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 policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and in the NIH Guide for 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 polity. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. 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: asknih@odrockm1.od.nih.gov. The program announcement title and number must be typed on line 2 of the face page of the application form, and the YES box must be marked. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete 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 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 their written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. * Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? * 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? * Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? * Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? * Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: * The reasonableness of the proposed budget and duration in relation to the proposed research. * The adequacy of plans to include both genders, minorities, and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. * 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. * Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States, or which provide augmentation of existing U.S. resources (for foreign applications only). 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 * Program priority INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Huber R. Warner, Ph.D. Biology of Aging Program National Institute on Aging Gateway Building, Suite 2C231 Bethesda, MD 20892-9205 Telephone: 301/496-6402 FAX: 301/402-0010 Email: warnerh@exmur.nia.nih.gov Bradley C. Wise, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 Bethesda, MD 20892-9205 Telephone: 301/496-9350 FAX: 301/496-1494 Email: wiseb@exmur.nia.nih.gov Sonia Skarlatos, Ph.D. NIH/NHLBI/DHVD Two Rockledge Center, Room 10186 6701 Rockledge Drive, MSC 7956 Bethesda, MD 20892-7956 Telephone: 301/435-0550 FAX: 301/480-2858 Email: skarlats@gwgate.nih.nhlbi.gov Kenneth A. Gruber, Ph.D. Division of Human Communication National Institute on Deafness and Other Communication Disorders Executive Plaza South, Room 400-C 6120 Executive Boulevard MSC 7180 Bethesda, MD 20892-7180 Telephone: 301/402-3458 FAX: 301/402-6251 Email: Kenneth_Gruber@nih.gov Linda S. Brady, Ph.D. Molecular and Cellular Neuroscience Research Branch National Institute of Mental Health Parklawn Building, Room 11C-06 5600 Fishers Lane Rockville, MD 20857 Telephone: 301/443-5288 FAX: 301/443-4822 Email: lb@helix.nih.gov Eugene J. Oliver, Ph.D. Division of Stroke, Trauma, and Neurodegenerative Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 806 7550 Wisconsin Avenue Bethesda, MD 20892-9150 Telephone: 301/496-5680 FAX: 301/480-1080 Email: eo11c@nih.gov Direct inquiries regarding fiscal and administrative matters to: Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 Bethesda, MD 20892-9205 Telephone: 301/496-1472 FAX: 301/402-3672 Mr. William Darby Grants Operations Branch National Heart, Lung and Blood Institute Two Rockledge Center, Room 7128 6701 Rockledge Drive, MSC 7128 Bethesda, MD 20892-7956 Telephone: 301/435-0177 FAX: 301/480-3310 Email: William Darby@nih.gov Sharon Hunt Chief, Grants Management Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-B, MSC 7180 Bethesda, MD 20892-7180 Telephone: 301/402-0909 FAX: 301/402-1758 Email: Hunts@msmail.nidcd.nih.gov Diana Trunnel Assistant Chief, Grants Management Branch National Institute of Mental Health 5600 Fishers Lane, Room 7C-08 Rockville, MD 20857 Telephone: 301/443-2805 Pat Driscoll Grants Management Specialist Grants Management Branch, DEA National Institute of Neurological Disorders and Stroke Federal Building, Room 1004 7550 Wisconsin Avenue Bethesda, MD 20892-9190 Telephone: 301/496-9231 FAX: 301/402-0219 Email: pd23n@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93-866 (NIA) and 93-242 (NIMH). Awards are under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under 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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