GENETIC MODIFICATION/ALTERNATIVE SOURCES OF STEM CELL

Project: Research project

Project Details

Description

The overall goal of this program is to develop strategies for the
correction of inherited diseases of bone marrow-derived cells by genetic
modification of hematopoietic stem cells. The specific aims of this
proposal are focused on the use of recombinant retroviral and adeno-
associated virus (AAV) vectors for gene transfer into primitive
hematopoietic stem cells. The specific diseases targeted are severe
combined immunodeficiency (adenosine deaminase deficiency), X-linked
chronic granulomatous disease (CGD), and hemoglobinopathies. Protocols
will be developed for the efficient transduction of human hematopoietic
stem cells with retroviral and AAV vectors. The relative merit of
different sources of human hematopoietic stem cells as targets for these
viral vectors will be evaluated. The feasibility of incorporating ex
vivo expansion to increase the number of stem cell targets will also be
investigated. Finally, recombinant viral vectors will be identified that
result in high level, stable, and functional expression of the transduced
gene in progeny of hematopoietic stem cells. Experimental approaches
will include the use of in vitro culture systems, xenogenic animal
models, and a murine model of X-linked CGD. The implementation of these
aims will be shared among 3 projects and 4 core units. This proposal
draws from a group of investigators with diverse but complementary
experience in hematopoiesis and stem cell biology, retroviral- and AAV-
mediated gene transfer, molecular genetics, virology, bone marrow
transplantation, and neonatology. Achievement of these goals will permit
the translation of this basic work to the development of clinical
protocols for effective viral-mediated gene transfer therapy of genetic
blood diseases. On a broader level, these studies should provide insight
into the biologic behavior of hematopoietic stem cells and the ability
to manipulate them ex vivo. The long term goal of this program at
Indiana University is the ability to correct in situ defective gene
sequences in hematopoietic stem cells, and use ex vivo expansion of
corrected stem cells in transplantation protocols.
StatusFinished
Effective start/end date9/30/948/31/06

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $915,000.00
  • National Institutes of Health
  • National Institutes of Health: $915,000.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $915,000.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $915,000.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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