DRUG DISCOVERY FOR THE TREATMENT OF ALZHEIMER"S DISEASE

Release Date:  January 8, 1999

PA NUMBER:  PAS-99-034 (Reissued, see PAS-05-022)

P.T.

National Institute on Aging
National Institute of Mental Health

PURPOSE

The National Institute on Aging (NIA) and the National Institute of Mental Health
(NIMH) invite qualified researchers to submit research grant applications
directed toward the discovery of novel compounds for the treatment of the
cognitive impairment and behavioral symptoms associated with Alzheimer"s disease
(AD).

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, Drug Discovery for the Treatment
of Alzheimer"s Disease, 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) or at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic 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 program project
(P01) grants. Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

The mechanisms of support for this Program announcement will be the National
Institutes of Health (NIH) research project grant (R01) and program project grant
(P01). Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant. The total project period for an
application submitted in response to this PA may not exceed five years.

FUNDS AVAILABLE

At least $1.5 million will be committed by the NIA in FY 1999 and FY 2000 to fund
applications of high scientific merit submitted in response to this Program
Announcement. Although this program is provided for in the financial plans of the
NIA and the NIMH, the award of grants pursuant to this PA is also contingent upon
the availability of funds for this purpose.

RESEARCH OBJECTIVES

I. BACKGROUND

Alzheimer"s disease (AD) is one of the most persistent and devastating dementing
disorders of old age, because it eventually leads to a complete loss of memory
and of the ability to function independently.  It is estimated that up to four
million people in the United States have AD in its various stages at an estimated
cost to society of $90 billion per year, and it is projected that 14 million
people could be victims of Alzheimer"s disease by the middle of the next century.

The disease presents enormous problems not only to affected individuals but also
to their families and raises many complex social and economic issues for the
country.

AD provides a complex neurobiological puzzle. Its etiology is not known, and the
pathobiological processes that underlie the steady progression of the clinical
course of this disease are not yet completely understood.  It is clear, however,
that mechanisms of cell to cell communication are disrupted.  These involve
several different types of neurotransmitter, neuropeptide, and neuromodulator
systems, neurochemical processes, protein trafficking, and elements of oxidative
and cellular energy metabolism processes.  The hallmark of the disease involves
progressive cell dysfunction, cell loss, and the accumulation of a variety of
abnormal protein and cytoskeletal abnormalities.  At present it is still not
known when and how the degenerative process begins, although a role in this
process involving the amyloid precursor protein and amyloid beta protein as well
as neurofibrillary pathology associated with the protein tau seems reasonable.

At present there are no generally safe and effective treatments for the cognitive
and behavioral symptoms of AD. The few agents that are currently approved by the
Food and Drug Administration have demonstrated only modest effects in modifying
the disease symptoms for relatively short periods in subsets of patients, and
none has shown an effect on disease progression.  The majority of the compounds
considered candidate drugs have generally been designed to affect the synthesis,
release, or degradation of neurotransmitters.  Most of the agents available thus
far have been targeted towards the cholinergic system which is an especially
vulnerable neural population in AD and cognitive function.

The NIA, NIMH and other NIH Institutes currently support extramural and
intramural projects for the study of the epidemiology, etiology, diagnosis, and
treatment of AD.  Notwithstanding these efforts, the increasing numbers of
affected individuals, the unknown etiology, the emotional, social, and economic
costs to the victims, caregivers, and society, and the fact that there is no
compound which can uniformly slow or reverse the progression of the disease or
ameliorate the cognitive and behavioral symptoms, all require that the most
creative scientific talents in all relevant scientific disciplines and
organizations be mobilized to aggressively pursue a concerted effort to discover
compounds and strategies for the treatment of the disease.  Although agents are
still needed which can ameliorate the symptoms of the disease even for a short
time (because such agents would provide needed relief, however brief, to the
victims and their families), new and novel efforts need to be focused on
compounds which can slow the disease progression, reverse the disease process,
and delay the onset of or prevent AD entirely.

II. RESEARCH OBJECTIVES AND SCOPE

The objective of this solicitation is to stimulate preclinical research in the
discovery, design, development and testing of novel compounds aimed at slowing,
halting, or, if possible, reversing the progressive decline in cognitive function
and modifying the behavioral symptoms in Alzheimer"s disease victims as well as
delaying the onset of or preventing AD. This initiative is intended to stimulate
basic research and development efforts. The goal is not to duplicate or compete
with pharmaceutical companies but to encourage, complement, and accelerate the
process of discovering new, innovative, and effective treatments for cognitive
impairment and behavioral symptoms in Alzheimer"s disease.

The development of compounds for ameliorating, modifying, or improving potential
aberrations in neuronal signal transduction pathways is encouraged.  These
treatments should be designed to affect fundamental processes of the neural
dysfunction and cell death associated with the disease by targeting steps of the
signal transduction pathway such as the cell membrane, second and third
messengers, protein phosphorylation, and signal amplification stages including
all facets of amyloid precursor protein, amyloid beta protein, and tau
neurobiology, as well as energy utilization, oxidative mechanisms, and
neurotrophin neurobiology.

Research directed toward drug discovery utilizing one or more of the following
examples or other novel approaches will be considered responsive to this PA.

1. Design and synthesis of compounds directed toward altering, modifying, or
regulating the following aspects of signal transduction mechanisms:

o  Membrane and cytoskeletal composition, structure and function,
o  Protein phosphorylation and dephosphorylation,
o  Channel function and structure,
o  Second and/or third messengers,
o  Gene expression or transcription,
o  Neurotrophic and growth promoting factors,
o  Mitochondrial function and cellular energy metabolism,
o  Oxidative metabolism,
o  Synthesis, trafficking, and degradation of nervous system proteins including
all facets of the neurobiology of amyloid precursor protein, amyloid beta
protein, and tau,
o  Ionic transport.

2. The isolation, identification and characterization of promising naturally
occurring products or synthetic chemical compounds.

3. Development of delivery systems to target compounds to the brain.

The above-mentioned areas of investigations are representative and not meant to
be inclusive. Investigators are encouraged to explore other avenues to identify
potential therapeutic agents.

Projects which include proposed animal model development or efficacy testing in
animal models must integrate these areas within the major goal of targeted drug
discovery.

Large-scale random screening of compounds will not be supported under this PA,
however, high-throughput screening of combinatorial chemical libraries may
qualify for support.

Extensive studies required for the clinical development of identified potential
treatments, such as toxicological testing, are beyond the scope of this PA.

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
sub-populations 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 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23,
Number 11, March 18, 1994 available on the web at the following URL address:
http://www.nih.gov/grants/guide/notice-files/not94-105.html

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may provide additional information concerning the
policy.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

It is the policy of 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 scientific 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:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

NOTE FOR APPLICATIONS FOCUSED ON AGING RESEARCH

Applications received in response to this program announcement are expected to
focus on scientific issues related to aging and to aging-related aspects of
disease. In describing the plan to recruit human subjects, investigators may cite
a focus on aging or on aging-related aspects of disease as the justification for
why children will be excluded. In this regard applicants may use Justification
1, the research topic to be studied is irrelevant to children, from the policy
announcement.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) 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, or 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. Applications are also available on the World Wide Web at
http://www.nih.gov/grants/funding/phs398/phs398.html

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.

Applicants planning to submit an investigator-initiated new (type 1), competing
continuation (type 2), competing supplement, or any amended/revised version of
the preceding grant application types requesting $500,000 or more in direct costs
for any year are advised that he or she must contact the Institute or Center (IC)
program staff before submitting the application, i.e, as plans for the study are
being developed. Furthermore, the applicant must obtain agreement from the IC
staff that the IC will accept the application for consideration for award.
Finally, the applicant must identify, in a cover letter sent with the
application, the staff member and Institute or Center who agreed to accept
assignment of the application.  Refer to the NIH Guide for Grants and Contracts,
March 20, 1998 at http://www.nih.gov/grants/guide/notice-files/not98-030.html

Submit the signed, original, single-sided application, along with five exact,
single-sided copies and five collated sets of appendix materials to:

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)

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 the
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.  Note that the application does not need to be
strong in all categories to be judged likely to have 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.

o  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?

o  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?

o  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?

o  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)?

o  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?

The initial review group will also examine: the appropriateness of proposed
project budget and duration, the adequacy of plans to include both genders,
children and minorities and their subgroups as appropriate for the scientific
goals of the research, or the justification for their exclusion, plans for the
recruitment and retention of subjects, the provisions for the protection of human
and animal subjects, and the safety of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  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:

Neil S. Buckholtz, Ph.D.
National Institute on Aging
Neuroscience and Neuropsychology of Aging Program
Gateway Building
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  Buckholn@exmur.nia.nih.gov

Linda S. Brady, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 11-97
Rockville, MD  20857
Telephone: (301) 443-9875
FAX: (301) 443-4822
Email: LB@helix.nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Joseph Ellis
National Institute on Aging
Grants and Contracts Management Office
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email: Joseph_Ellis@nih.gov

Ms. Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone: (301) 443-2805
FAX: (301) 443-6885
Email: Diana_Trunnell@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.866 (NIA) and No. 93.242 (NIMH).  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.

Note that there is a new publication of the NIH Grants Policy Statement published
in the NIH Guide for Grants and Contracts on October 21, 1998 and available at
http://www.nih.gov/grants/guide/notice-files/not98-146.html

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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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