IN UTERO STEM CELL TRANSPLANTATION FOR GENETIC DISEASES

NIH Guide, Volume 22, Number 15, April 16, 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



The RESEARCH OBJECTIVES for RFA HL-93-014 were incorrectly transmitted

in the electronic NIH Guide, Vol. 22, No. 14, April 9, 1993.  The

corrected version appears below.



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 utero

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) early expression of 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.



Exclusions



Epidemiological studies, large-scale clinical trials, and large

multi-project grant applications (program project grants) are

specifically excluded from this RFA.



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