Full Text PAR-97-002
NIH GUIDE, Volume 25, Number 35, October 18, 1996
PA NUMBER:  PAR-97-002
P.T. 34

  Metabolic Diseases 
  Gene Therapy+ 

National Institute of Diabetes and Digestive and Kidney Diseases
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites applications for pilot and feasibility studies
proposing innovative strategies for gene therapy vector development.
These grants will allow investigators to obtain preliminary data on
novel approaches to gene therapy relevant to the treatment of genetic
metabolic diseases.  Topics for this Program Announcement will be
limited to pre-clinical vector development designed to increase the
level and the duration of gene expression in vivo.  Research designed
to elucidate the basic mechanisms and cellular factors involved in
the processes of vector entry and transgene expression will also be
responsive to this announcement.
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).
Applications may be submitted by domestic and foreign for-profit and
nonprofit 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 will be supported through the exploratory/developmental
grants (R21) mechanism.  These awards are to demonstrate feasibility
and obtain preliminary data.  Thus, these grants will not be
renewable; continuation of projects developed under this program will
be through the research grant program. Projects will be limited to
$100,000 direct costs per year and are limited to two years duration.
The NIDDK anticipates initiating an ongoing program making five
awards each year in response to this Program Announcement contingent
on the receipt of applications of sufficient scientific merit.
Gene therapy was originally envisioned as a method to permanently
replace defective genes for the treatment of genetic diseases. To
achieve this goal, a method of gene delivery must be efficient and
have the ability to provide long-term, high-level expression in order
to attain therapeutic levels of most proteins.  Although many
advances have been made toward this goal, none of the vector systems,
retroviral, adenoviral or plasmids delivered by liposomes, currently
being tested has all of these attributes.   Research is needed to
improve aspects of current vector systems as well as to investigate
novel vector systems in order to make permanent genetic correction an
attainable goal.
On December 6, 1995, the NIDDK conducted a Workshop entitled, "AAV
Vectors: Gene Transfer into Quiescent Cells."  The Workshop explored
the potential applications for one novel vector system, AAV, which
exhibits many desirable characteristics for treatment of metabolic
diseases.  Many directions for future research were enumerated in
this Workshop which have been summarized in a meeting report in Human
Gene Therapy 7:1615-1619, 1996. Participants stressed the importance
of studying vectors in vivo which often provides results different
from those predicted by studies in cell lines.
Although this Workshop was focused on AAV vectors, it served as a
prototype for the problems encountered by investigators developing
any new vector system.  This Workshop identified the need for a
mechanism to address research questions for new vector systems where
feasibility had not yet been determined.  Other examples of new
vectors systems whose potential are being investigated for gene
therapy include vectors based on Herpes Simplex virus, Epstein Barr
virus, Lentivirus and Foamy virus.
Last year the Director of NIH convened "The Panel To Assess the NIH
Investment in Research on Gene Therapy." The members expressed their
concern that new and novel methods need to be developed and this
effort needs to be fostered by the NIH.  They recommended the use of
pilot and feasibility grants to help stimulate this process. The
NIDDK currently supports pilot and feasibility studies associated
with each of its funded Gene Therapy Centers.  This Program
Announcement would make a similar opportunity available to all
The purpose of this Program Announcement is to allow investigators to
test new approaches where there are limited preliminary data but a
strong rationale.  This limited award is designed to allow
investigators to demonstrate feasibility and 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 which are critical for the treatment of
genetic metabolic diseases by proposing either novel modifications of
currently used vectors or novel vectors. Areas of emphasis for vector
development include:
o  Improving the duration of transgene expression in vivo;
o  Improving capability of transducing non-dividing cells;
o  Developing methods to improve transduction/transfection
o  Developing methods to target vectors to specific cell types in
o  Developing markers for selection of transduced cells in vivo;
o  Improving regulation and increasing levels of gene expression by
the use 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 cellular factors required for vector entry,
trafficking, integration, and expression.
Applications will be accepted at the standard application deadlines
as indicated in the application kit.  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, or may be obtained from the Grants Information
Office, Office of Extramural Outreach and Information Resources,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail:
The program announcement title, "Pilot Studies on Gene Therapy
Vectors for Metabolic Diseases" and number PAR-97-002 must be typed
on line 2 of the face page of the application form and the YES box
must be marked.
The completed original application and five legible copies must be
delivered to:
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
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 by the 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 National Diabetes and Digestive and Kidney
Diseases Advisory Council.
The National Heart, Lung and Blood 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 these Institutes are encouraged to
contact the appropriate program staff.  If questions of program
overlap arise for a given application, the DRG Referral Guidelines
will prevail in the Institute assignment of the application.  Some
applications may receive multiple assignment.
The following review criteria will be used to assess the scientific
merit of an application:
o  novelty of the research proposed;
o  scientific, technical, or medical significance of proposed
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
o  availability of the resources necessary to perform the research;
o  appropriateness of the proposed budget for the proposed research;
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.
Applications will compete for available funds with all other approved
applications assigned to the National Institute of Diabetes and
Digestive and Kidney Diseases. 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 Balance within the areas of research covered by the Program
Applicants are encouraged to discuss the relevance of their proposal
to this 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) 480-3508
Email:  McKeonC@ep.niddk.nih.gov
Direct inquiries regarding fiscal and administrative matters to:
Donna Huggins
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 center Drive, Room 6AN-49K, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8848
Email:  HugginsD@ep.niddk.nih.gov
This program is described in the Catalog of Federal Domestic
Assistance No. 93.847.  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
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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