GENE TRANSFER APPROACHES TO ENHANCE ISLET TRANSPLANTATION

Release Date:  September 20, 2001

RFA:  RFA-DK-02-020

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov/)
National Institute of Allergy and Infectious Diseases
 (http://www.niaid.nih.gov/)

Letter of Intent Receipt Date:  November 15, 2001
Application Receipt Date:       December 12, 2001

THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  MODULAR 
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS 
THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED 
IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases and the 
National Institute of Allergy and Infectious Diseases are soliciting 
applications to develop gene transfer approaches to enhance islet 
transplantation.  Type 1 diabetes results from the immune destruction of the 
pancreatic beta-cell.  Several protocols are being tested that treat this 
disease by transplantation of islets.  One of the major barriers to 
implementing this approach is the limited supply of islets for 
transplantation.  Ex vivo gene transfer approaches could be one method to 
engineer beta-cells or alter islets to enhance viability that could have 
advantages for transplantation.  NIDDK and NIAID are soliciting pilot and 
feasibility grants to explore gene transfer techniques that could be applied 
to enhanced islet transplantation.

HEALTHY PEOPLE 2010

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 Transfer Approaches to Enhance Islet 
Transplantation, is related to the priority area of Diabetes and Chronic 
Disabling Conditions.  Potential applicants may obtain a copy of "Healthy 
People 2010" at http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

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 investigator.

MECHANISM OF SUPPORT

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.  The total project period for an application submitted 
in response to this RFA may not exceed 2 years.

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is September 30, 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

The NIDDK and NIAID intend to commit approximately $2,000,000, provided for 
research on type 1 diabetes by Section 931 of the Benefits Improvement and 
Protection Act of 2000, in FY 2002 to fund 10 to 12 new grants in response to 
this RFA.  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, including indirect 
(Facilities and Administration) costs on consortium arrangements.  Because 
the nature and scope of the research proposed may vary, it is anticipated 
that the size of each award will also vary. Although the financial plans of 
the NIDDK and NIAID 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.

RESEARCH OBJECTIVES

Background

Type 1 diabetes is estimated to affect 1 million Americans many of them 
children.  These individuals must adhere to a regimen of life-long dietary 
restriction, glucose monitoring and insulin administration and even the most 
rigorous effort is not sufficient to normalize glucose levels.  Major 
mortality and morbidity are from the long-term complications of the disease 
including blindness, neuropathy, renal and cardiovascular disease.  Recently, 
promising results have been achieved in a several patients with islet 
transplantation using a new combination of drugs that prevent rejection and 
halt autoimmune destruction of transplanted islets.  While these results are 
promising, the long-term toxicity of these drugs is unknown and a major 
obstacle to the wide-spread application of this treatment is the limited 
supply of islets. 

Novel approaches are needed to develop new sources of beta-cells or islets 
for transplantation and to enhance their viability.  Gene transfer is one 
method that can be used to alter the properties of somatic cells.  Recently, 
several viral vectors, especially the lentiviral and AAV vectors, have shown 
promise for introducing genes into beta-cells.  Using these gene transfer 
techniques, beta-cells with new properties can be developed to enhance 
transplantation.

Objectives and Scope

Several possible approaches could be used to alter the properties of cells to 
develop islets for transplantation.  One approach is to engineer beta-cells 
with regulated growth promoting genes to permit expansion in vitro.  Human 
beta-cell lines have been developed using the oncogenes, SV40 T antigen and 
H-ras.  However, these lines are unlikely to be suitable for clinical use 
because of the presence of the oncogene.  An elegant technique has been 
described in hepatocytes to excise the growth promoting oncogene prior to 
transplantation using a cre/lox site-specific recombination system.  Similar 
approaches could be applied to beta-cells

Another potential source of beta-cells is to derive beta-cells from other 
tissues by introducing genes that induce transdifferentiation of beta-cells.  
For example, the expression of PDX1 in hepatocytes and exocrine pancreas 
results in markers of beta-cell differentiation. This approach could 
facilitate the establishment of beta-cells from cells that already grow well 
in culture.  Recently, hematopoietic stem cells have demonstrated greater 
plasticity to develop along other lineages than previously believed.  These 
would also be a source of cells that may be able to be manipulated to 
differentiate to beta-cells by expressing genes that control the 
developmental program. 

In addition, the beta-cells could be engineered to be more resistant to 
immune destructive and apoptotic signals prior to transplantation. This could 
reduce the number of cells that need to be transplanted as well as reduce the 
need for immunosuppression.  Modification of the histocompatibility markers 
on beta-cells would result in cells that generate a reduced immune response.  
Using gene transfer techniques to blocking apoptotic pathways could produce 
beta-cells that have a survival advantage after transplantation.  Another 
approach to reducing the number of beta-cells needed is to introduce a gene 
that could be used to apply selective pressure to give transplanted beta-
cells a selective growth advantage in vivo. 

In addition to altering the properties of the transplanted cells, gene 
transfer techniques could be used to modulated the immune system of the 
subject prior to transplantation.  Most patients with type 1 diabetes have 
developed antibodies to beta cell markers.  Gene transfer techniques can be 
used to induce tolerance for beta-cell markers or to alter immune regulatory 
cells to reduce the risk of transplant rejections.

Since these are preliminary studies to explore the appropriate use of this 
new technology and to demonstrate its feasibility, the NIDDK and NIAID are 
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. Some of 
the approaches that need to be explored are enumerated below. Relevant topics 
listed below are only examples and should not be construed as required or 
limiting:

o Investigate the use of growth promoting genes to derive beta-cells that 
can be expanded in culture while maintaining or reintroducing the 
differentiated phenotype for transplantation.

o Derive beta-cells from other tissues or progenitor cells by introducing 
genes needed to develop the differentiated beta-cell phenotype.

o Engineer beta-cells that have enhanced resistance to immune destructive 
or apoptotic signals.

o Engineer beta-cells that elicit a reduced or altered immune response.

o Investigate the use of gene transfer for immunomodulation to reduce the 
need for immunosuppression and reduce islet transplant rejection 

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 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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  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.

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://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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.

REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS

All investigators proposing research involving human subjects should read the 
policy that was published in the NIH Guide for Grants an Contracts, June 5, 
2000 (Revised August 25, 2000), and is available at the following URL address 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
URLS IN NIH GRANT APPLICATIONS OR APPENDICES
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.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT

The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

LETTER OF INTENT 

Prospective applicants are asked to submit, by November 15, 2001, 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 submitted.

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. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format. Although applicants are strongly 
encouraged to begin using the 5/2001 revision of the PHS 398 as soon as 
possible, the NIH will continue to accept applications prepared using the 
4/1998 revision until January 9, 2002. Beginning January 10, 2002, however, 
the NIH will return applications that are not submitted on the 5/2001 
version.  For further assistance contact GrantsInfo, Telephone 301/435-0714, 
Email: GrantsInfo@nih.gov.

All application instructions outlined in the PHS 398 (rev. 5/01) application 
kit are to be followed, with the following modifications:  

1.  Applicants MUST cite the RFA number on line 2 of the application.  
Applicants are strongly urged to contact the Program Directors listed in the 
INQUIRIES section prior to submission of an application, for advice about 
eligibility and responsiveness. 

2.  R21 applications will use the “MODULAR GRANT” and “JUST-IN-TIME” 
concepts, with direct costs requested in $25,000 modules, up to the total 
direct costs limit of $100,000 per year. 

3. Although preliminary data are not required for an R21 application, they 
may be included.

4.  Sections a-d of the Research Plan may not exceed 15 pages, including 
tables and figures.  

5. Appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to circumvent 
the page limit for the research plan.   Copies of appendix material will only 
be provided to the primary reviewers of the application and will not be 
reproduced for wider distribution.  The following materials may be included 
in the appendix:

o Up to five publications, including manuscripts (submitted or accepted 
for publication), abstracts, patents, or other printed materials 
directly relevant to the project.  These may be stapled as sets.
o Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.
o Original glossy photographs or color images of gels, micrographs, etc., 
provided that a photocopy (may be reduced in size) is also included 
within the 15 page limit of items a-d of the research plan.  

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

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 NIH staff.  The research grant application form PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  Applicants are permitted, 
however, to use the 4/1998 revision of the PHS 398 for scheduled application 
receipt dates until January 9, 2002.  If you are preparing an application 
using the 4/1998 version, please refer to the step-by-step instructions for 
Modular Grants available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.  Additional 
information about Modular Grants is also available on this site.

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  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 RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

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. 752 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 Administrator.  

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 critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK.  Incomplete applications will be returned to the 
applicant without further consideration. If the application is not responsive 
to the RFA, NIDDK or CSR staff may contact the applicant to determine whether 
to return the application to the applicant or submit it for review in the 
competition with unsolicited applications at the next review cycle.
 
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.

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 technologies? 

(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 any)?

(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 
research.

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.

Schedule
Letter of Intent Receipt Date:    November 15, 2001
Application Receipt Date:         December 12, 2001
Peer Review Date:                 February 2002
Council Review:                   May 30-31, 2002
Earliest Anticipated Start Date:  July 1, 2002

AWARD CRITERIA

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

o Scientific merit as determined by peer review;
o Availability of funds;
o Programmatic priorities.

INQUIRIES

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
E-mail: cm67w@nih.gov

Shiv A. Prasad, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 5255
Bethesda, MD  20892-7640 (20817 for express mail deliveries)
Telephone:  (301) 496-5598
FAX:  (301) 402-2571
Email:  sp89j@nih.gov

Direct inquiries regarding fiscal matters to:

Mary Kay Rosenberg
National Institute of Diabetes and Digestive and Kidney Diseases
Division of Extramural Activities 
6707 Democracy Boulevard, Rm. 722 MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8891 
FAX: (301) 480-3504
E-mail:  mr239s@nih.gov

Pamela G. Fleming
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 2119
Bethesda, MD  20892-7614
Use Zip Code 20817 for overnight deliveries
Telephone:  (301) 402-6580
FAX:   (301) 480-3780
Email:  pf49e@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.847 and 93.855.  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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