PILOT STUDIES TO DEVELOP NOVEL SYSTEMS FOR GENE DELIVERY

Release Date:  Febuary 11, 1998

PA NUMBER:  PAR-98-026

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Mental Health

Application Receipt Date:  June 9, 1998

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
and the National Institute of Mental Health (NIMH) invite applications for
pilot and feasibility studies proposing innovative strategies for gene
delivery that could ultimately lead to treatments for genetic metabolic
diseases including cystic fibrosis.  This program announcement replaces
PAR-97-002 published October 18, 1996.  This ongoing program is designed to
permit investigators to obtain preliminary data on novel approaches to gene
therapy.  This program will be supported through the exploratory/developmental
grant (R21) mechanism.  Topics for this Program Announcement will be limited
to pre-clinical studies designed to increase the level and the duration of
gene expression in vivo.  Research to elucidate the basic mechanisms and
cellular factors involved in the processes of vector entry and gene expression
will also be responsive to this program announcement.

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.  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.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as principal
investigators.  

This program enables investigators to explore the feasibility of a concept
related to gene therapy of metabolic diseases and generate sufficient data to
pursue it through other funding mechanisms.  The pilot and feasibility studies
are intended to: (1) provide initial support for new investigators; (2) allow
exploration of possible innovative new leads or new directions for established
investigators in gene therapy; and (3) stimulate investigators from other
areas to lend their expertise to research in this area.  Pilot and feasibility
grants are not intended to support or supplement ongoing funded research of an
established investigator.

MECHANISM OF SUPPORT

This program will be supported through the exploratory/developmental grant
(R21) mechanism. These awards are to demonstrate feasibility and obtain
preliminary data testing innovative ideas that represent clear departure from
ongoing research interests. These grants will not be renewable; continuation
of projects developed under this program will be through the regular research
project grant program. Projects will be limited to $100,000 direct costs per
year and are limited to two years duration.

The NIDDK has an ongoing program consisting of up to 10 awards each year. 
Funding of applications received in response to this Program Announcement will
be contingent on the receipt of applications of sufficient scientific merit.

RESEARCH OBJECTIVES

Background

Although the principle of delivering genes to a cell and repairing a defect in
a metabolic pathway has been demonstrated in vitro, translating this basic
finding into providing life-long correction to patients with genetic diseases
has proven to be extremely difficult.  In order to provide sustained
correction, the gene must be delivered to either a non-dividing, long-lived
cell or a stem cell that will continually transmit the gene to its progeny. 
Alternatively, transient correction could prove therapeutic if the regimen
could be administered repeatedly.  In both cases, it is necessary to avoid
detection by the immune system, which recognizes the viral and sometimes the
therapeutic protein as foreign, extinguishing their expression and producing
antibodies, which interfere with readministration.  The initial attempts at
gene therapy for genetic metabolic diseases have revealed basic gaps in our
knowledge on the mechanisms of vector entry, gene expression and immune
surveillance.

The vectors currently under investigation have a variety of properties that
may be useful for some gene therapy applications.  Viral vectors derived from
adeno-associated virus, lentivirus and adenovirus can infect non-dividing
cells and under some circumstances provide long-term expression.  Retroviruses
can transduce dividing cells and provide long-term expression but at low
frequencies.  Lipoplexes have provided mostly transient expression but may be
amenable to strategies for targeted delivery and for evading the immune
system.  Other components such as the use of an appropriate promoter may be
critical to the development of sustained, tissue-specific and/or regulated
gene expression.  Clearly, more work is needed to explore novel methods and
novel combinations to develop regimens for long-term gene correction for
genetic metabolic diseases.

Delivery of genes to treat brain disorders poses unique problems.  It requires
efficient targeting of delivery vehicles across the blood-brain barrier to
transfect fully differentiated, post-mitotic cells with a variety of
phenotypes, as well as their multipotential progenitors.  Direct
administration of vectors into the brain may cause problems associated with
cytotoxicity and physical tissue damages.  For these reasons, development of
efficient delivery methodologies, as well as the design and testing of
appropriate promoters, may be critical to developmental patterns of tissue- or
cell- type specific gene expression. 

The NIDDK initiated this Pilot and Feasibility Program in FY 1997 to provide a
mechanism to fund innovative approaches to gene therapy applicable to genetic
diseases.  The NIDDK supports an integrated program of cystic fibrosis and
metabolic disease research through regular research, program project,
Specialized Centers of Research (P50), and Gene Therapy Core Center (P30)
grants.  NIMH supports research on delivery methodologies to target brain
regions and nuclei that regulate cortical development and plasticity, emotion,
cognition, memory, and behavior.

Objectives

The purpose of this Program Announcement is to allow investigators to test new
approaches where there are limited preliminary data but a strong rationale and
a reasonable expectation of feasibility.  This limited award is designed to
allow investigators to obtain the preliminary data necessary for a regular
research grant.  Applications for pilot projects and feasibility studies
should be aimed at improving those aspects of gene therapy that are critical
to ultimately treat genetic metabolic diseases by proposing either novel
modifications of currently used vectors or development of novel systems for
gene delivery.  Areas of research emphasis include:

o  Developing new and non-conventional delivery systems;

o  Developing novel methods to extend the duration of transgene expression in
vivo;

o  Developing novel methods for transduction of non-dividing cells;

o  Developing methods to improve transduction/transfection efficiency;

o  Developing methods to target vectors to specific cell types in vivo;

o  Developing methods to enhance efficiency of gene delivery across the
blood-brain barrier;

o  Developing markers for selection of transduced cells in vivo;

o  Developing novel regimens for repeat administration of viral and non-viral
vectors;

o  Developing new systems for regulated, inducible or cell-type specific gene
expression encompassing the investigation of novel promoters, enhancers and
locus control regions;

o  Developing methods for site-specific integration including more efficient
methods of homologous integration; and

o  Determining the host cellular factors required for efficient vector entry,
trafficking, integration, and expression.

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 new 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, 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 policy.

APPLICATION PROCEDURES

Applications will be accepted on a single receipt date of June 9, 1998. 
Applications are to be submitted on the 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 301-435-0714,
email: asknih@od.nih.gov.

The program announcement title, "Pilot Studies to Develop Novel Systems for
Gene Delivery" and the number of this PA must be typed on line 2 of the face
page of the application form and the YES box must be marked.

Mail 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)

The National Heart, Lung and Blood Institute; the National Cancer Institute;
the National Institute of Child Health and Human Development; and the National
Institute of Neurological Disorders and Stroke have an interest in supporting
new approaches to gene therapy.  Applicants interested in developing gene
delivery systems applicable to the mission of these Institutes are encouraged
to contact the appropriate program staff.  If questions of program overlap
arise for a given application, the PHS Referral Guidelines will prevail in the
Institute assignment of the application.  Some applications may receive
multiple assignment.

REVIEW CONSIDERATIONS

Applications that are complete will be evaluated for scientific and technical
merit by an appropriate peer review group convened by NIDDK 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 review, comments on the following aspects of the application will
be made 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 the assignment of the overall score.

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?  Does this work represent a significant departure from
the investigators ongoing funded research? 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?

o  Appropriateness of the proposed budget and duration in relation to the
proposed research.

 o  Adequacy of plans to include both genders and 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.  

o  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.

The initial review group will also examine 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 assigned to the National Institute of Diabetes and Digestive and
Kidney Diseases and the National Institute of Mental Health.  The following
will be considered in making funding decisions:

o Innovation
o Quality of the proposed project as determined by peer review
o Availability of funds
o Program priority
o Balance among the scientific areas covered by this program announcement.

INQUIRIES

Applicants are encouraged to discuss the relevance of their proposal to this
program announcement prior to submission.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Catherine McKeon, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN.18B - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8810
FAX:  (301) 480-3503
Email:  Catherine_McKeon@nih.gov

Steven O. Moldin, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 10C-26
Rockville, MD  20857
Telephone:  (301) 443-2037
FAX:  (301) 443-9890
Email:  smoldin@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Ms. Denise Payne
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8845
Email:  PayneD@extra.niddk.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.
93.847 (NIDDK) 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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