Full Text DK-94-001


NIH GUIDE, Volume 22, Number 35, October 1, 1993

RFA:  DK-94-001

P.T. 34

  Gene Therapy+ 
  Metabolic Diseases 
  Biology, Molecular 
  Nucleic Acids 

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  January 26, 1994
Application Receipt Date:  February 23, 1994


The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the National Institute of Neurological Diseases and
Stroke, (NINDS) invite investigators to submit innovative research
applications for the development or improvement of techniques focused
on achieving successful human gene therapy for the treatment of
metabolic diseases.  The ultimate goal of this program is to extend
the repertoire of diseases that can be successfully treated by gene
therapy.  The diseases of interest include disorders of cellular
transport, disorders of lysosome metabolism, peroxisome metabolism,
amino acid and organic acid metabolism, carbohydrate metabolism,
purine and pyrimidine metabolism, metal metabolism, lipid metabolism,
and mucopolysaccharide metabolism.  Many of these diseases require
the ability to deliver DNA to diverse tissue types.  This program
will support regular research grants as well as limited feasibility
studies for new, highly innovative aspects of gene therapy.


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 Request
for Applications (RFA), New Methods of Gene Therapy for Genetic
Metabolic Diseases, is related to the priority areas of infant health
and chronic disabling conditions.  Potential applicants may obtain a
copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).


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.
Minority individuals and women are encouraged to submit as Principal


Support of this program will be through the NIH research project
grant (R01) award.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the
applicant.  Except as otherwise stated in this announcement, awards
will be administered under Public Health Service (PHS) grants policy
as stated in the PHS Grants Policy Statement.

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 total requested project period
for applications submitted in response to this RFA may not exceed
five years.  A maximum of three-years will be requested for foreign
awards.  The maximum dollar request is limited to $160,000 in direct
costs for the initial budget period.  Budgets should be commensurate
with the degree of development of the proposal and the supporting
preliminary data.  High risk applications should reflect the
experimental nature of the work by requesting a reduced budget and a
shorter duration.  Applications with a more developed hypothesis
supported by preliminary data may request budgets up to the cap.  The
anticipated average amount of the direct costs awards is $130,000.


For FY 1994, $2,000,000 will be committed by the NIDDK and $500,000
by the NINDS to fund applications submitted in response to this RFA.
It is anticipated that approximately 12 awards will be made.
However, this funding level is dependent upon the receipt of a
sufficient number of applications of high scientific merit.
Applicants must limit their requests to not more than $160,000 direct
costs for the initial budget period.  Although this program is
provided for in the financial plans of the NIDDK and NINDS, the award
of grants pursuant to this RFA is also contingent upon the
availability of funds for this purpose.


The purpose of this initiative is to stimulate innovative research
applications addressing the areas of gene therapy that are the
roadblocks to treatment of genetic metabolic diseases.  This
initiative is an important addition to a broad program for the
development or improvement of therapies for metabolic diseases
including cystic fibrosis and degenerative neurological diseases such
as gangliosidoses and other neuronal storage diseases.


Genetic diseases taken together account for substantial morbidity and
mortality.  It has been estimated that 200,000 babies are born each
year with a genetic disease.  Since these disorders manifest a
variety of serious symptoms including in many cases brain
degeneration, debilitating illness and premature death, they
represent a substantial burden in both health care costs and human
suffering for the patients and their families.  For many of these
diseases no effective treatment is currently available and gene
therapy remains the only hope.

Recent advances have made the first clinical trials of gene therapy
for the treatment of genetic metabolic diseases in humans a reality.
The success of these studies has unleashed active research toward the
applications of this new technology to other genetic diseases.
Although the general principles will be applicable to the treatment
of many diseases, specific problems may have to be addressed to apply
the technology to any particular disease.  To date, a variety of
approaches have been studied in humans including ex vivo retroviral
correction of B and T cells for adenosine deaminase deficiency, ex
vivo correction of hepatocytes for hypercholesterolemia and in vivo
adenovirus correction of lung epithelium for cystic fibrosis.  These
approaches represent only a few of the multiple possibilities because
for each individual disease the treatment must be tailored to include
expression of a specific gene, targeting to the appropriate affected
organ and, ideally, reproduction of the unique pattern of
tissue-specific expression.

Through its investigator-initiated research and program project
grants, NIDDK supports research on the etiology, pathophysiology and
treatment of inherited metabolic diseases including cystic fibrosis.
The NIDDK has provided funding for research that has identified the
gene responsible for cystic fibrosis and the genes responsible for
many of the inherited metabolic diseases.  These discoveries are the
prerequisite for gene therapy.  NIDDK is planning to fund two Core
Centers devoted to research on gene therapy of cystic fibrosis and
other genetic diseases (P30).  These centers are designed to foster
collaboration and to accelerate the progress of moving gene therapy
from the laboratory to the clinic.

The NINDS supports research on many neurogenetic disorders. This
includes research on metabolic disorders where the main focus is on
nervous system involvement.  Gene therapy in neurological disorders
is complicated by the difficulty in transporting material across the
blood-brain-barrier.  The NINDS supports an active portfolio on
research to identify disease genes and their mechanisms of action, to
develop new and innovative therapies for treatment of theses
diseases.  Currently, NINDS supports a multi-center clinical trial
for bone marrow transplant treatment of several neuronal storage

Objectives and Scope

Although individual diseases have particular problems that will need
to be resolved, there are some general problems that have impeded the
progression of gene therapy from the laboratory to the patient.  Some
of these problems include the inability to maintain high levels of
expression for indefinite periods of time in a variety of tissues,
the inability to infect terminally differentiated cells and the
infrequent targeting of a gene into its normal locus.  Experiments
designed to solve these basic problems in gene therapy would advance
the whole field.

The area of gene therapy for metabolic diseases has evolved quickly.
In order to further accelerate progress, many new directions must be
evaluated quickly for their feasibility as approaches for gene
therapy.  Studies of new viral vectors, chimeric vectors and
improvement in delivery vehicles such as liposomes and
receptor-mediated endocytosis would be some examples of areas in need
of further development.  Therefore, this program featuring the option
of a limited award for the study of the feasibility of new approaches
is being announced.  Applications proposing innovative new approaches
that, if successful, would have profound implications for advancing
gene therapy will be considered even with limited preliminary data.

Specific areas of interest include, but are not limited to:

(1) Improving technology of gene transfer including increasing the
frequency of transfection with special emphasis on transfection into
terminally differentiated cells.

(2) Development of vectors and tissue-specific promoters that will
increase the level and duration of gene expression in the breadth of
tissues affected in genetic diseases.

(3) Improving our understanding of factors responsible for programmed
shutoff of introduced genes and development of methods to overcome
this problem especially for Adenovirus Vectors.

(4) Development of improved packaging cell lines for the production
of high titer recombinant viruses including retrovirus,
adeno-associated virus (AAV) and herpes virus.

(5) Improving methods of maintaining relevant cells in culture and
for transplantation of corrected cells to appropriate organs.

(6) Identification, isolation, transfection and reimplantation of
stem cells or methods to specifically target stem cells in vivo for
gene transfer to organs including the brain, liver, lung, and muscle.

(7) Development of technology to insert recombinant DNA at an
increased frequency at specific chromosomal locations.

(8) Improved delivery of DNA using vehicles such as liposomes and
receptor mediated endocytosis.

(9) Specific strategies for delivery of material across the
blood-brain barrier.

The above examples are by no means intended to restrict the range of
research but to illustrate some areas of interest.  Prospective
applicants are encouraged to propose other topics of relevance to
achieving successful gene therapy for inherited metabolic diseases.



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them. This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size must be appropriate for the scientific
objectives of the study.  This information must be included in the
form PHS 398 (rev. 9/91) in Item 4 (Research Design and Methods) of
the Research Plan AND summarized in Item 5, Human Subjects.
Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations; i.e., Native
Americans [including American Indians or Alaskan Natives],
Asian/Pacific Islanders, African Americans, Hispanics.

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention [and preventive strategies], diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and reflected
in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants that do not comply with these policies.


Prospective applicants are asked to submit, by January 26, 1994, 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 subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIDDK and NINDS staff to estimate the
potential review workload and to avoid possible conflict of interest
in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 594-7515


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  The form is available from most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/710-0267.  The RFA label available in the PHS 398
application form must be affixed to the bottom of the face page.
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, on item 2a of the face page of the
application, applicants must check the YES box and enter:  "RFA: New
Methods of Gene Therapy for Genetic Metabolic Diseases, RFA number

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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional copies of the application must
also be sent under separate cover to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

Applications must be received by February 23, 1994.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) will
not accept any application in response to this announcement that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  However, it is
allowable to submit the same project as both an R01 and as a
component project of a program project.  The DRG 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.  Such applications must not only
include an introduction addressing the previous critique but also be
responsive to this RFA.  The National Heart, Lung and Blood Institute
and the National Institute of Child Health and Human Development also
have an interest in supporting areas of research covered by this RFA.
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.


Upon receipt, applications will be initially reviewed by the Division
of Research Grants (DRG) for completeness.  Incomplete applications
will be returned to the applicant without further consideration.
Evaluation for responsiveness to the program requirements and
criteria stated in the RFA is an NIDDK and NINDS staff function.  If
the application is not responsive to the RFA, NIDDK and NINDS staff
will contact the applicant to determine whether it should be returned
to the applicant, or held until the next regular receipt date and
reviewed in competition with all other applications.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NIDDK.
Applications may be subjected to triage by an NIDDK peer review group
to determine their scientific merit relative to other applications
received in response to this RFA.  If the number of applications is
large compared to the number of awards to be made, a preliminary
scientific peer review may be conducted and applications withdrawn
from further competition when they are not competitive for the award.
The NIDDK will notify the applicant and institutional official of
this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an initial review group specifically convened
for this RFA by the NIDDK.  Following this review, the applications
will be given a secondary review by the NDDK Advisory Council and/or
NNDS Advisory Council unless not recommended for further
consideration by the initial review group.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific/technical merit criteria specific to the objectives of
the RFA;

o  scientific, technical, or medical significance and originality of
proposed research;

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 resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed-means for protecting against or minimizing such effects.

o  if a foreign grant, uniqueness of research such that it can only
be performed outside of the United States.


Funding decisions will be made based on the initial review group and
national advisory council recommendations, program relevance, and
availability of funds.


Written and telephone inquiries concerning this RFA are encouraged.
Inquiries regarding programmatic issues may be directed to:

Dr. Catherine McKeon
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 621
Bethesda, MD  20892
Telephone:  (301) 594-7582
FAX:  (301) 594-9011

Dr. Judy A. Small
Division of Convulsive, Developmental and Neuromuscular Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8C04
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-5821
FAX:  (301) 402-0887

Inquiries regarding fiscal matters may be directed to:

Ms. Donna Huggins
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 594-7543

Mr. King P. Bond, Jr.
Division of Extramural Affairs
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219


Letter of Intent Receipt Date:  January 26, 1994
Application Receipt Date:       February 23, 1994
Initial Review:                 June 1994
Second Level Review:            September 1994
Anticipated Date of Award:      September 30, 1994


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


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