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Blood, 15 December 2000, Vol. 96, No. 13, pp. 4111-4117
GENE THERAPY
Stable in vivo expression of glucose-6-phosphate
dehydrogenase (G6PD) and rescue of G6PD deficiency in stem cells by
gene transfer
Ana Rovira,
Maria De
Angioletti,
Olga Camacho-Vanegas,
Delong Liu,
Vittorio Rosti,
Humilidad F. Gallardo,
Rosario Notaro,
Michel Sadelain, and
Lucio Luzzatto
From the Department of Human Genetics, Memorial
Sloan-Kettering Cancer Center, New York, NY.
Many mutations of the housekeeping gene encoding
glucose-6-phosphate dehydrogenase (G6PD) cause G6PD deficiency in
humans. Some underlie severe forms of chronic nonspherocytic
hemolytic anemia (CNSHA) for which there is no definitive treatment. By using retroviral vectors pseudotyped with the vesicular stomatitis virus G glycoprotein that harbor the human G6PD (hG6PD) complementary DNA, stable and lifelong expression of hG6PD was obtained in all the
hematopoietic tissues of 16 primary bone marrow transplant (BMT)
recipient mice and 14 secondary BMT recipients. These findings demonstrate the integration of a functional gene in totipotent stem
cells. The average total G6PD in peripheral blood cells of these
transplanted mice, measured as enzyme activity, was twice that of
untransplanted control mice. This allowed the inference that the amount
of G6PD produced by the transduced gene must be therapeutically
effective. With the same vectors both the cloning efficiency and the
ability to form embryoid bodies were restored in embryonic stem cells,
in which the G6PD gene had been inactivated by targeted
homologous recombination, thus effectively rescuing their
defective phenotype. Finally, expression of normal human G6PD in
hG6PD-deficient primary hematopoietic cells and in human hematopoietic cells engrafted in nonobese diabetic/severe combined immunodeficient mice was obtained. This approach could cure severe CNSHA caused by G6PD deficiency.
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