Release Date:  August 30, 2000

RFA:  DK-01-006

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Allergy and Infectious Diseases
National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  October 16, 2000
Application Receipt Date:       November 16, 2000



The National Institute of Diabetes and Digestive and Kidney Diseases, the 
National Institute of Allergy and Infectious Diseases, and the National 
Heart, Lung and Blood Institute are soliciting applications to develop 
gene therapy approaches for the treatment of diabetes and/or its 
complications.  Gene therapy is a promising technology to introduce 
exogenous genes into somatic cells that will alter the cell’s properties.  
On November 8 and 9, 1999, the NIDDK and NIAID along with other 
Institutes sponsored a meeting entitled, “Gene Therapy Approaches for 
Diabetes and Its Complications,” to discuss possible approaches for using 
gene therapy to treat either diabetes or its complications.  One of the 
recommendations from the meeting was to support additional studies to 
develop novel approaches using gene therapy for the treatment of diabetes 
and its complications.   


The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a 
PHS-led national activity for setting priority areas.  This Request for 
Applications (RFA), Gene Therapy Approaches for Diabetes and Its 
Complications, is related to the priority areas of Diabetes and Chronic 
Disabling Conditions.  Potential applicants may obtain a copy of "Healthy 
People 2010" at


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 enables investigators to explore the feasibility of a 
concept related to gene therapy of diabetes 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 


This RFA will use the National Institutes of Health (NIH) 
exploratory/developmental grant (R21) award mechanism.  Responsibility 
for the planning, direction, and execution of the proposed project will 
be solely that of the applicant.  An applicant may request a project 
period of up to 2 years and a budget for direct costs of up to $100,000 
per year.
This RFA is a one-time solicitation.  These grants are not renewable; 
continuation of projects developed under this program will be through the 
regular research grant program and will compete with all investigator-
initiated applications and be reviewed according to the customary peer 
review procedures.  The anticipated award date is July 1, 2001.


The NIDDK, NIAID, and NHLBI intend to commit a total of approximately 
$2,000,000 ($1,000,000 from the Balanced Budget Act of 1997 and 
$1,000,000 from the NIDDK appropriation) in FY 2001 to fund 12 to 15 new 
grants in response to this RFA.  Although the financial plans of the 
NIDDK, NIAID, and NHLBI provide support for this program, awards pursuant 
to this RFA are contingent upon the availability of funds and the receipt 
of a sufficient number of applications of outstanding scientific and 
technical merit.  At this time, it is not known if this RFA will be 



Over the last ten years, gene therapy techniques have been developed for 
introducing genes into somatic cells that alter the properties of these 
cells.  Recently, several successful reports suggest that gene therapy 
may be an appropriate treatment for certain conditions.  There are many 
approaches to interfering with the development of type 1 diabetes and to 
treating the complications resulting from both type 1 and type 2 diabetes 
that would appear to be amenable to gene therapy technology.  The purpose 
of this RFA is to encourage development of gene therapy approaches for 
type 1 diabetes and its complications and to test these in appropriate 
animal models or small pilot studies.

On November 8 and 9, 1999, the NIDDK, NIAID, NHLBI, NCRR, JDFI and ADA 
sponsored a meeting entitled, “Gene Therapy Approaches for Diabetes and 
Its Complications,” to discuss some possible approaches for using gene 
therapy to treat either diabetes or its complications.  The Summary and 
Recommendations from that conference can be found on the NIDDK Web page 
at  One of the 
recommendations from that meeting was to support the development of 
additional approaches using gene therapy for the treatment of diabetes 
and its complications.  Since these are preliminary studies to explore 
the appropriate use of this new technology and to demonstrate its 
feasibility, the NIDDK is using the exploratory/developmental grant 
mechanism.  These grants can be used to demonstrate the feasibility of an 
approach and to develop preliminary data for a future regular research 
grant submission.  This mechanism allows investigators to test new 
approaches where there are limited preliminary data but a strong 
rationale and a reasonable expectation of feasibility.  

Type 1 diabetes results from the immune destruction of the beta cells in 
the pancreas.  Therefore, methods that interfere with the development of 
autoimmunity or the immuno-destructive process would prevent the 
development of type 1 diabetes.  There seems to be sufficient 
understanding of type 1 diabetes immune mediated beta-cell killing to 
devise gene therapy approaches that interrupt the inflammatory process.  
It may also be possible to interfere directly with the apoptotic pathways 
within the beta cell that result in its death.  This use of gene therapy 
will not correct a defective genetic makeup but rather will interrupt the 
progression of disease pathogenesis.

Fundamental research could focus on induction of immunologic tolerance. 
For example, DNA-based vaccine approaches should be explored as a method 
of providing expression of autoantigens to induce tolerance.  Preclinical 
work has already tested the hypothesis that the genetic manipulation to 
express autoantigens will reduce beta-cell self reactivity. This approach 
would be applicable to prevention of type 1 diabetes.

Gene therapy can be applied as an intervention for type 1 diabetes.  
Research utilizing T cell homing technologies to deliver immune 
suppressive cytokines or other factors at the site of the inflammation is 
a very exciting prospect.  This is an important area of research that may 
yield therapeutic modalities that would interfere with progressive 
inflammatory diseases, including beta-cell killing in type 1 diabetes.  
It would seem that the antigen or epitope specificity of the immune 
system with respect to the use of either antibodies, T cells or both has 
not been fully explored for disease protection and inhibition of 
progressive autoimmunity diseases.  The gene therapy technology would 
involve both ex vivo and in vivo approaches.

Another potential approach to prevent the development of diabetes is to 
prevent apoptosis of the beta-cell by targeting protective genes into the 
pancreas in vivo.  These could include tissue-specific expression of 
immune suppressive cytokines and apoptotic genes.  These techniques could 
also be employed to protect transplanted pancreatic beta-cells or 
transplanted islets from autoimmune destruction, allograft rejection or 
both.  Ongoing research at the preclinical level suggests that islets 
expressing certain ligands or immune suppressive cytokines have an 
improved survival.  This is a novel and hitherto uncharted area of 
research that deserves further exploration.  

Recently, a novel approach of generating beta cells in vivo has been 
tested in an animal model.  The introduction of the transcription factor, 
PDX1, into hepatocytes resulted in the transdifferentiation of 
hepatocytes to beta-cells (Nature Medicine 6:568-572, 2000).  The 
exploration of this and other transdifferentiation strategies may also 
yield novel ways to treat type 1 diabetes.

Long-term complications of diabetes include nephropathy, retinopathy, 
neuropathy, accelerated cardiovascular disease, impaired wound healing, 
altered gastrointestinal and bladder function, and periodontal disease. 
Since glucose management remains a difficult problem, complications from 
diabetes continue to be a high priority area for development of novel 
treatments.  Gene therapy approaches seem promising in the selected areas 
of micro and macro vascular disease, neuropathy and wound healing.  
Several of these studies are progressing to phase I clinical trials.  One 
approach expressed the growth factor, VEGF, locally to grow new blood 
vessels for the treatment of vascular disease.  Another approach used the 
introduction of the growth factor, PDGF, into diabetic ulcers to 
accelerate wound healing.  These and other gene therapy approaches to 
treat these conditions need to be explored.

Scope and Objectives

Applications should focus on the development of gene therapy approaches 
for the treatment of type 1 diabetes and its complications.  Although 
delivery of insulin by gene therapy is one possible method to treat 
diabetes, this approach is complicated by the requirement for rapid and 
tight regulation of insulin secretion to glucose levels. Such studies may 
be premature with our current technology. Relevant topics listed below 
are examples and should not be construed as required or limiting.  
o To investigate gene therapy strategies to induce tolerance to beta-cell 

o To investigate novel strategies such as T-cell homing to deliver 
immunosuppressive genes

o To investigate altering cytokine gene expression in order to suppress 
the inflammatory process

o To develop vectors that are targeted to the pancreatic beta-cell to 
deliver genes that interfere with its immunodestruction 

o To investigate the expression of protective genes in beta-cells to 
prevent immunodestruction

o To explore the use of altered expression of other genes in the glucose 
metabolic pathway for their therapeutic potential to complement the 
effects of insulin

o To investigate expressing genes involved in mouse and human beta-cell 
differentiation to determine their role in transdifferentiation of cell 
types such as hepatocytes and pancreatic duct cells

o To develop strategies to prevent and/or delay the onset of 
complications such as the targeted expression of growth factors

o To investigate the expression of genes that may regulate wound healing

o To investigate the expression of genes to prevent and/or delay the 
onset of peripheral vascular diseases

o To develop gene therapy approaches to alter the expression of the 
receptors for Advanced Glycated Endproducts

o To develop gene therapy methodologies to effectively treat various 
complications and validate them in relevant animal models

o To develop carefully designed pilot clinical gene therapy studies for 
diabetic complications.


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 are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as 
Subjects in Clinical Research," published in the NIH Guide for Grants and 
Contracts on 
August 2, 2000 
a complete copy of the updated Guidelines are available at  
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to provide a 
description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including 
subgroups if applicable; and b) all investigators to report accrual, and 
to conduct and report analyses, as appropriate, by sex/gender and/or 
racial/ethnic group differences.


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:

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

All applications and proposals for NIH funding must be self-contained 
within specified page limitations. Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no 
obligation to view the Internet sites. Reviewers are cautioned that their 
anonymity may be compromised when they directly access an Internet site.


Prospective applicants are asked to submit, by October 16, 2000, a letter 
of intent that includes a descriptive title of the proposed research; the 
name, address, and telephone number of the Principal Investigator; the 
identities of other key personnel and participating institutions; and the 
number and title of the RFA in response to which the application may be 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that 
it contains allows NIDDK staff to estimate the potential review workload 
and plan the review.

The letter of intent is to be sent to:

Chief, Review Branch 
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 653 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms 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:

The modular grant concept establishes specific modules in which direct 
costs may be requested as well as a maximum level for requested budgets. 
Only limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award.  It is anticipated that these 
changes will reduce the administrative burden for the applicants, 
reviewers, and Institute staff.  The research grant application form PHS 
398 (rev. 4/98) is to be used in applying for these grants, with the 
modifications noted below.


Modular Grant applications will request direct costs in $25,000 modules, 
up to a total direct cost request of $100,000 per year.  The total direct 
costs must be requested in accordance with the program guidelines and the 
modifications made to the standard  PHS 398 application instructions 
described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $100,000) and Total Costs 
[Modular Total Direct plus Facilities and Administrative (F&A) costs] for 
the initial budget period.  Items 8a and 8b should be completed 
indicating the Direct and Total Costs for the entire proposed period of 

Page 4 of the PHS 398. It is not required and will not be accepted with 
the application.

categorical budget table on Form Page 5 of the PHS 398.  It is not 
required and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION:  Prepare a Modular Grant Budget 
Narrative page. (See 
for sample pages.)  At the top of the page, enter the total direct costs 
requested for each year.  This is not a Form page.

o Under Personnel, list all project personnel, including their names, 
percent of effort, and roles on the project. No individual salary 
information should be provided. However, the applicant should use the NIH 
appropriation language salary cap and the NIH policy for graduate student 
compensation in developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded 
to the nearest $1,000.  List the individuals/organizations with whom 
consortium or contractual arrangements have been made, the percent effort 
of key personnel, and the role on the project.  Indicate whether the 
collaborating institution is foreign or domestic.  The total cost for a 
consortium/contractual arrangement is included in the overall requested 
modular direct cost amount.  The Letter of Intent should include 
information on establishing a consortium. 

Provide an additional narrative budget justification for any variation in 
the number of modules requested.

o BIOGRAPHICAL SKETCH:  The Biographical Sketch provides information used 
by reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required 
for all key personnel, following the instructions below.  No more than 
three pages may be used for each person. A sample biographical sketch may 
be viewed at:

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations.

o CHECKLIST:  This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the 
type of agreement and the date. All appropriate exclusions must be 
applied in the calculation of the F&A costs for the initial budget period 
and all future budget years.

o The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review.  

The RFA label available in the PHS 398 (rev. 4/98) application form must 
be affixed to the bottom of the face page of the application.  Failure to 
use this label could result in delayed processing of the application such 
that it may not reach the review committee in time for review.  In 
addition, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked.

The sample RFA label available at: has been 
modified to allow for this change. Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed photocopies, in one package 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)

At time of submission, two additional copies of the application must be 
sent to:

Chief, Review Branch
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 653 MSC 5452
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)

Applications must be received by the application receipt date listed in 
the heading of the RFA.  If an application is received after that date, 
it will be returned to the applicant without review. Supplemental 
documents containing significant revision or additions will not be 
accepted, unless applicants are notified by the Scientific Review 

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  The CSR will not accept any application that is essentially 
the same as one already reviewed.  This does not preclude the submission 
of substantial revisions of applications previously reviewed, but such 
applications must include an introduction addressing the previous 


Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDDK, NIAID, and NHLBI.  Incomplete 
applications will be returned to the applicant.  

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NIDDK in accordance with the review criteria 
stated below.  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 the 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 
Allergy and Infectious Diseases Advisory Council and the National Heart, 
Lung, and Blood Advisory Council.

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.

(1) 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?

(2) 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?

(3) Innovation:  Does the project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does the project 
challenge existing paradigms or develop new methodologies or 

(4) 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 

(5) 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:

o  Adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also 
be evaluated. 

o  The reasonableness of the proposed budget and duration to the proposed 

o  The adequacy of the proposed protection of humans, animals, or the 
environment, to the extent that they may be adversely affected by the 
project proposed in the application.

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.

Letter of Intent Receipt Date:    October 16, 2000
Application Receipt Date:         November 16, 2000
Peer Review Date:                 February/March 2001
Council Review:                   May 30-31, 2001
Earliest Anticipated Start Date:  July 1, 2001


Award criteria that will be used to make award decisions include:

o Scientific merit as determined by peer review;
o Innovation;
o First time NIH awardee;
o Availability of funds;
o Programmatic priorities.


Inquiries concerning this RFA are encouraged.  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
6707 Democracy Boulevard, Rm. 6103 MSC 5460
Bethesda, MD 20892-5460
Telephone:  (301) 594-8810
FAX: (301) 480-3503

Elaine Collier, MD  
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Room 5135 MSC 7640
Bethesda, MD 20892-7640
Telephone:  (301) 496-7104
FAX:  (301) 402-2571

Sonia I. Skarlatos, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10186, MSC7940
Bethesda, Maryland 20892-7940
Telephone: (301) 435-0545
FAX: (301) 480-2849

Direct inquiries regarding fiscal matters to:

Denise Payne
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 626 MSC 5456
Bethesda, MD 20892-5456
Telephone:  (301) 594-8845 
FAX: (301) 480-3504

Mary Ledford
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 2249, MSC 7614
Bethesda, MD 20892-7614
Telephone: (301) 402-6446
FAX: (301) 493-0597

Jane Davis
Division of Extramural Activities
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7174, MSC 7926
Bethesda, Maryland 20892-7926
Telephone: (301) 435-0166
FAX: (301) 480-3310


These programs are described in the Catalog of Federal Domestic 
Assistance No. 93.847, 93.855, and 93.837.  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 NIH grants policies and Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92.  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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