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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