Full Text HL-93-014

IN UTERO STEM CELL TRANSPLANTATION FOR GENETIC DISEASES

NIH Guide, Volume 22, Number 14, April 9, 1993

RFA:  HL-93-014

P.T. 34

Keywords: 
  Blood Diseases 
  Transplantation of Organs 
  Disease Model 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  October 1, 1993
Application Receipt Date:  November 17, 1993

PURPOSE

The Cellular Hematology Branch, Division of Blood Diseases and
Resources, National Heart, Lung, and Blood Institute (NHLBI), invites
applications for studies that may contribute to the development of
methodologies to perform in utero hematopoietic stem cell transplants
to cure genetic blood diseases that can both be diagnosed in utero and
are curable by postnatal marrow transplantation.  The specific focus
will be on animal models, but human studies will also be considered.

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.  This Request
for Applications (RFA), In Utero Stem Cell Transplantation for Genetic
Diseases, is related to the priority areas of Cooley's anemia, sickle
cell anemia, other genetic blood diseases, and hematopoietic stem cell
transplantation.  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 202-782-3238).

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.  Awards
in response to this RFA will be made to foreign institutions only for
research of very unusual merit, need, and promise, and in accordance
with PHS policy governing such awards.  Foreign institutions are not
eligible for First Independent Research Support and Transition (FIRST)
(R29) awards.  Applications from minority individuals and women are
encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) and FIRST (R29) awards and is a one-time
solicitation.  Applicants, who will plan and execute their own research
programs, are requested to furnish their own estimates of the time
required to achieve the objectives of the proposed research project.
Up to five years of support may be requested.  Applicants for FIRST
awards must request five years of support.  At the end of the official
award period, renewal applications may be submitted for peer review and
competition for support through the regular grant program of the NHLBI.
It is anticipated that support for the present program will begin in
July 1994.  Administrative adjustments in project period and/or amount
of support may be required at the time of the award.  All current
policies and requirements that govern the research grant programs of
the National Institutes of Health will apply to grants awarded in
connection with this RFA.  Since a variety of approaches would
represent valid responses to this announcement, it is anticipated that
there will be a range of costs among individual grants awarded.

FUNDS AVAILABLE

Although the financial plans for fiscal year 1994 include $1.5 million
for this program, award of grants pursuant to this RFA is contingent
upon receipt of funds for this purpose.  It is anticipated that about
six new grants will be awarded under this program.  The specific amount
to be funded will, however, depend on the merit and scope of the
applications received and on the availability of funds.  If
collaborative arrangements involve sub-contracts with other
institutions, the NHLBI Grants Operations Branch (telephone
301-594-7436) should be consulted regarding procedures to be followed.

RESEARCH OBJECTIVES

In the past twenty years, allogeneic bone marrow transplantation
increasingly has become used as a cure for a variety of genetic defects
of the hematopoietic and immune systems and for lysosomal storage
diseases.  Genetic diseases that have been successfully cured by bone
marrow transplantation include Cooley's anemia, sickle cell anemia,
Fanconi anemia, Blackfan-Diamond anemia, severe combined
immunodeficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia,
infantile agranulocytosis, Chediak-Higashi disease, chronic
mucocutaneous candidiasis, mucopolysaccharidosis, cartilage-hair
hypoplasia, Gaucher's and other storage diseases.  Some of these
diseases, such as Cooley's anemia (beta-thalassemia) and sickle cell
anemia, are major worldwide public health problems.  Others are
devastating orphan diseases that are extremely costly to treat.
Genetic diseases that cause death in utero, such as homozygous
alpha-thalassemia, may also possibly be cured by in utero stem cell
transplantation.  Collectively, these diseases occur in
tens-of-thousands of births per year.

However, conventional bone marrow transplantation has several
drawbacks:  (1) only about 35 percent of transplant candidates will
have a suitably matched marrow donor; (2) the long-term effects of the
preparative regimen of lethal doses of irradiation and/or cytotoxic
drugs are not known; (3) post-transplant complications such as
infection and graft-versus-host disease are significant and contribute
to the morbidity and mortality of the procedure; (4) for some diseases,
the disease process has caused irreversible damage prior to the
transplant; and (5) the significant cost of the procedure which could
be as much as $250,000, not including the possible long-term care for
chronic graft-versus-host disease.

In the sheep and monkey animal models, recent progress seems to
indicate that donor fetal liver hematopoietic stem cells can be
successfully transplanted into an unrelated pre-immune recipient fetus.
After birth, the chimeric animals still appear healthy and normal up to
five years post-transplant.  This procedure has been performed without
the need for tissue matching, without marrow ablation, without
immunosuppressive drugs, and without the development of
graft-versus-host disease.  This suggests that the fetus is both an
ideal recipient and donor of hematopoietic stem cells, as has recently
been demonstrated by the long-term engraftment and expression of human
stem cells in preimmune sheep fetuses.

In a number of diseases (e.g., storage diseases), an early expression
of donor cells activity (i.e., soon after transplant and before birth)
is a critical requirement since even at birth significant clinical
disease exists.  In diseases such as Cooley's anemia and other
hemoglobinopathies, a higher level of donor cell engraftment is needed
to be of therapeutic benefit.  In this regard, recent findings of
improved donor hematopoietic stem cell engraftment as the result of
homing receptor manipulations by growth factors are promising.  The
technical and quality control issues that are involved when fetal donor
stem cells are used may limit the applicability of this source of stem
cells.  Although in animal studies and in limited clinical studies,
T-depleted adult stem cells have failed to engraft adequately in utero.
The significant progress in stem cell purification and characterization
provides for new sources of donor stem cells.  Moreover, the
possibility of employing in vitro expanded fetal or adult stem cells
for use in in utero transplants has not been explored.

The possibility now exists for correcting genetic diseases in utero,
without the significant problems that were described above for bone
marrow transplantation.  Therefore, this initiative is for the
development of methodologies to perform in to perform in to ppero
hematopoietic stem cell transplants to cure genetic diseases that can
be diagnosed in utero and that are curable by postnatal marrow
transplantation.

Examples of Areas of Interest

The following are only examples and prospective applicants are urged to
use their own ideas as to the area of research on which to focus.  The
major areas that need further investigation before the procedure can be
applied in clinical practice include, among others: (a) improved donor
cell engraftment; (b) en oy expresssf donor cell activity; (c) the use
of alternate sources of donor stem cells, such as fetal liver, adult
peripheral blood, adult bone marrow, and hematopoietic stem cells that
have been expanded in culture; and (d) quality control issues regarding
the collection, processing, storage and use of donor hematopoietic stem
cells.

Disciplines and Expertise

Among the disciplines and expertise that may be appropriate for this
program are hematology, immunology, cell biology, medicine, and
neonatology.ith no exclusions from the base for training-related
expenses.

RESEARCH OBJECTIVES

The Minority Institutional Research Training Program is designed to
offer research training grant awards in cardiovascular, pulmonary, and
hematologic research to minority schools to enable qualified graduate
students, health professional students, and postdoctoral students to
participate in research programs.  It is expected to attract students
in the developmental stages, increase awareness of these diseases, and
to acquaint them with career opportunities in research.

The Minority Institutional Research Training Program is intended to:

o  Train graduate students, health professional students, and
postdoctoral students at minority schools that have the potential to
develop a meritorious program in cardiovascular, pulmonary, or
hematologic research for research careers in areas relevant to these
diseases.

o  Stimulate cardiovascular, pulmonary, and hematologic diseases and
hematologic resources research, prevention, control, and education by
offering minority school graduate students, health professional
students, and postdoctoral students the opportunity to enhance their
research capabilities in these areas.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398
(rev. 9/91).  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
(301) 710-0267.  The title and number of the RFA must be typed in
section 2a on the face page of the application.

The completed original application and three legible copies must be
sent or delivered to:

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

Two additional copies of the application must be sent to:

Scientific Review Administrator
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 550
Bethesda, MD  20892

Applications must be received by November 17, 1993.

REVIEW PROCEDURES

All applications responding to this announcement will be reviewed for
scientific and technical merit by the Research Training Review
Committee of the Division of Extramural Affairs, NHLBI, followed by a
second level review by the National Heart, Lung, and Blood Advisory
Council.

The factors to be considered in the evaluation of the proposed training
program are:

o  Adequacy of faculty, facilities, and resources for the proposed
research training, both at the minority institution and the research
center;

o  Adequacy of the cooperative arrangements between the minority
institution and the research program;

o  Commitment of the relevant faculty and the two institutions to the
goals of the training program;

o  Procedures for evaluation of the impact of the program on the
trainees involved.

AWARD CRITERIA

Applications will compete for available funds with other approved
applications assigned to the National Heart, Lung, and Blood Institute.
The following will be considered in making funding decisions:

o  Scientific and technical merit of the application as determined by
peer review
o  Availability of funds
o  Program balance among the research areas of the announcement

INQUIRIES

Written and telephone inquires are encouraged.  Guidelines for this
program may be obtained from any of the following:

John Fakunding, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 3C04
Bethesda, MD  20892
Telephone:  (301) 496-1724

Fann Harding, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 5A08
Bethesda, MD  20892
Telephone:  (301) 496-1817

Mary Reilly, M.S.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Westwood Building, Room 640A
Bethesda, MD  20892
Telephone:  (301) 594-7466

For fiscal and administrative matters, contact:

Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A15C
Bethesda, MD  20892
Telephone:  (301) 594-7434

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
Nos. 93.837, 93.838, and 93.839.  Awards will be made under the
authority of the Public Health Service Act, Title III, Section 301
(Public Law 78-410, as amended; 42 USC 241) and administered under PHS
grants policies and Federal Regulations at 42 CFR Part 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.

.

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	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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