Blood, 1 October 2002, Vol. 100, No. 7, pp. 2278-2278
Epo on demand
The development of safe and effective gene therapy poses many
formidable challenges. Some biomedical applications such as the
hemoglobinopathies require that the gene product be expressed in a
specific cell type, for example, erythroid progenitors. No such
constraint pertains when the gene product circulates in the plasma. But
in many cases, the level of the therapeutic protein needs to be tightly
regulated. Perhaps the most compelling example is the hotly pursued
goal of treating diabetes by a vector in which insulin gene expression
responds appropriately to changes in blood glucose. The closest
hematologic counterpart is the development of a vector in which
erythropoietin (Epo) production is induced by subtle physiologic
decreases in intracellular oxygen tension. Unlike the insulin gene,
wherein the transcriptional response to glucose is complex and
not well understood, the hypoxic induction by Epo depends upon a single
crucial hypoxia inducible (transcription) factor (HIF) that is
regulated by an elegant system of oxygen sensing and signal
transduction, shared by all cells.
Binley and colleagues (page 2406) exploit this transcriptional
servomechanism. They show quite convincingly that intramuscular injection of an adeno-associated virus harboring an EPO
gene driven by a promoter containing HIF-response
elements can cure severe anemia in mice in which endogenous Epo
production has been nearly eliminated. Normal hematocrit levels are
maintained for 7 months or more after initiation of treatment. The
remarkably tight oxygen-dependent regulation of the transduced
EPO gene is borne out by the total lack of change in
hematocrit when this vector is injected into healthy animals.
This strategy could lead to a muchimproved way of administering
recombinant human Epo (rhEpo) to patients. Long-term treatment with
thrice-weekly rhEpo is very costly, particularly in patients who
require relatively high doses. A key benefit of a physiologically regulated therapeutic gene is that enhanced production of Epo will
continue until the anemia is corrected and the tissue depot in which
the vector has been injected no longer senses hypoxia. But one note of
caution seems warranted. Mother Nature placed the major site of Epo
production in the subcortex of the kidney for a very good reason. At
this site, wide fluctuations in oxygen tension are dampened, and
therefore Epo production properly responds to total body hypoxia rather
than to local vicissitudes. Intramuscular injection of a regulatable
EPO gene could result in untoward increases in Epo
expression from local hypoxia induced by exercise. Further studies
in larger animal models are needed to investigate this potential problem and circumvent it.
H. Franklin Bunn
Harvard Medical School
