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Stimulation of erythropoiesis by in vivo gene therapy: physiologic
consequences of transfer of the human erythropoietin gene to experimental
animals using an adenovirus vector
Y Setoguchi, C Danel and RG Crystal
Pulmonary Branch, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, MD.
Erythropoietin (Epo), a 30.4-kD glycoprotein, is the principal regulator of
erythropoiesis. To evaluate the concept that in vivo gene transfer might be
used as an alternative to recombinant human Epo (rhEpo) in applications
requiring a 1- to 3-week stimulation of erythropoiesis, the
replication-deficient recombinant adenovirus AdMLP.Epo was constructed by
deleting the majority of E1 from adenovirus type 5, and replacing E1 with
an expression cassette containing the adenovirus type 5 major late promoter
(MLP) and the human Epo gene, including the 3' cis-acting hypoxia response
element. In vitro studies showed that infection of the human hepatocyte
cell line Hep3B with AdMLP.Epo resulted in a 15-fold increase in Epo
production in 24 hours that was enhanced to 116-fold in the presence of a
hypoxic stimulus. One-time in vivo administration of AdMLP.Epo (7 x 10(9)
plaque-forming units/kg) to the peritoneum of cotton rats caused a marked
increase in red blood cell production, with a 2.6-fold increase in bone
marrow erythroid precursors by day 4, and sevenfold increase in
reticulocyte count by day 7. The hematocrit increased gradually, with a
maximum of 64% +/- 4% at day 14 (compared with an untreated baseline of 46%
+/- 2%), and a level of 55% +/- 1% at day 24. Furthermore, one-time
subcutaneous administration of AdMLP.Epo caused an increase in hematocrit
that peaked at 14 days (57% +/- 2%) and was still elevated at day 42.
Hematocrit level in animals receiving subcutaneous administration of
AdMLP.Epo sustained a long-term increase compared with animals receiving
intraperitoneal administration. In the context of these observations, gene
therapy with a single administration of an adenovirus vector containing the
human EPO gene may provide a means of significantly augmenting the
circulating red blood cell mass over the 1- to 3-week period necessary for
many clinical applications.
Volume 84,
Issue 9,
pp. 2946-2953,
11/01/1994
Copyright © 1994 by The American Society of Hematology
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