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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1618-1624
GENE THERAPY
Lack of dominant-negative effects of a truncated  c on
retroviral-mediated gene correction of immunodeficient
mice
Makoto Otsu,
Kazuo Sugamura, and
Fabio Candotti
From the Clinical Gene Therapy Branch, National
Human Genome Research Institute, National Institutes of Health,
Bethesda, MD; and the Department of Microbiology and Immunology,
Tohoku University School of Medicine, Sendai, Japan.
A recent clinical trial of gene therapy for X-linked severe
combined immunodeficiency (XSCID) has shown that retroviral-mediated gene correction of bone marrow stem cells can lead to the development of normal immune function. These exciting results have been preceded by
successful immune reconstitution in several XSCID mouse models, all
carrying null mutations of the common gamma chain ( c). One question
not formally addressed by these previous studies is that of possible
dominant-negative effects of the endogenous mutant c protein on the
activity of the wild-type transferred gene product. The present work
was therefore undertaken to study whether corrective gene transfer was
applicable to an XSCID murine model with preserved expression of a
truncated c molecule ( c+-XSCID). Gene correction
of c+-XSCID mice resulted in the reconstitution of
lymphoid development, and preferential repopulation of lymphoid organs
by gene-corrected cells demonstrated the selective advantage of
c-expressing cells in vivo. Newly developed B cells showed
normalization of lipopolysaccharide-mediated proliferation and
interleukin-4 (IL-4)-induced immunoglobulin G1 isotype switching.
Splenic T cells and thymocytes of treated animals proliferated normally
to mitogens and responded to the addition of IL-2, IL-4, and IL-7,
indicating functional reconstitution of c-sharing receptors.
Repopulated thymi showed a clear increase of
CD4 /CD8 and CD8+
fractions, both dramatically reduced in untreated
c+-XSCID mice. These improvements were associated
with the restoration of Bcl-2 expression levels and enhanced cell
survival. These data indicate that residual expression of the
endogenous truncated c did not lead to dominant-negative effects in
this murine model and suggest that patient selection may not be
strictly necessary for gene therapy of XSCID.
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