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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2213-2220
GENE THERAPY
 Minor-globin messenger RNA accumulation in reticulocytes
governs improved erythropoiesis in thalassemic mice after
erythropoietin complementary DNA electrotransfer in
muscles
Selda Samakoglu,
Elena Fattori,
Stefania Lamartina,
Carlo Toniatti,
Daniel Stockholm,
Jean Michel Heard, and
Delphine Bohl
From Laboratoire Rétrovirus et Transfert
Génétique, CNRS URA 1930; Institut Pasteur, Paris,
France; IRBM, Pomezia, Italy; and Généthon III, CNRS
URA1923, Evry, France.
Mechanisms governing the induction of effective
erythropoiesis in response to erythropoietin (Epo) oversecretion have
been investigated in  thalassemic C57Bl/6Hbbth mice.
Naked DNA encoding an expression vector for mouse Epo was introduced
into skeletal muscles by electrotransfer. A transient increase of serum
Epo concentrations with a proportional augmentation of hematocrit
values was observed. Various parameters relevant to thalassemia were surveyed in blood samples taken before
treatment, at the peak of Epo secretion, and when the phenotype
reverted to anemia. We measured globin messenger RNA (mRNA)
levels in reticulocytes by real-time quantitative polymerase chain
reaction, globin chain synthesis levels, and several indicators of
erythrocyte membrane quality, including bound  chains, bound
immunoglobulins, main protein components, and iron
compartmentalization. Data indicated that high serum Epo levels
primarily affect minor-globin mRNA accumulation in reticulocytes.
Other changes subsequent to intense Epo stimulation, like increased
minor/-globin chain synthesis ratio, reduced levels of chains and immunoglobulins bound to membranes, improved
spectrin/band 3 ratio, increased red blood cell survival, and improved
erythropoiesis appeared as consequences of increased
minor-globin mRNA levels. This conclusion is consistent with models
postulating that intense Epo stimulation induces the expansion and
differentiation of erythroid progenitors committed to fetal
erythropoiesis. Although phenotypic correction was partial in mice, and
comparable achievements will probably be more difficult to
obtain in humans, naked DNA electrotransfer may provide a safe and
low-cost method for reassessing the potentials of Epo as an inducer of
fetal erythropoiesis reactivation in patients with thalassemia.
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D. A. Dean
Nonviral gene transfer to skeletal, smooth, and cardiac muscle in living animals
Am J Physiol Cell Physiol,
August 1, 2005;
289(2):
C233 - C245.
[Abstract]
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