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Anaemia Management
developed fatal hepatic necrosis that was temporally related to the EPO as a result of gene therapy is a potentially attractive area of research.
introduction of this compound.
23
Although investigations regarding causality There are a number of delivery systems that have been investigated for
are ongoing, the US Food and Drug Administration (FDA) has temporarily this purpose, including the injection of naked DNA,
28
adenovirus
suspended any further clinical trials with the HIF stabilisers. transfection,
29
use of artificial human chromosomes
30
and transplantation
of autologous or allogeneic cells manipulated ex vivo.
31
As with all gene
GATA Inhibition therapy, there are many hurdles to overcome before this strategy could
The GATA family is made up of six transcription factors – GATA 1–6. be used in humans. Not only would there need to be assurance regarding
GATA-2 inhibits EPO gene transcription by binding to the GATA sequence the absence of oncogenicity, but it would also be imperative to show that
on the EPO promoter, thereby leading to downregulation of EPO tight control of the activity of the transferred gene can be achieved. This
messenger RNA (mRNA) expression and subsequent EPO synthesis.
24
may be possible and one experiment in animals has shown that linking
Therefore, GATA-2 acts as a negative regulatory molecule of EPO gene the transgene to a hypoxia-responsive DNA element may establish
expression. Disrupting this negative signal is a potential future strategy in anoxygen-dependent feedback regulation of the transgene, similar to
producing an antianaemic agent. Several molecules are under that of the endogenous EPO gene.
32
investigation, including K-11706, which has been shown to enhance EPO
production both in vitro and in vivo.
25
Conclusions
New targets and strategies for stimulating erythropoiesis and treating
Haemopoietic Cell Phosphatase Inhibition anaemia have been developed in line with elucidation of the molecular
Another strategy with potential for enhancing erythropoiesis is targeting mechanisms controlling RC production. Following the introduction of
haemopoietic cell phosphatase (HCP, SHP-1).
26
This protein tyrosine recombinant human EPO, attempts were made to modify the molecule and
phosphatase is located in the cytoplasm of haemopoietic cells and causes produce longer-acting erythropoietic agents, such as darbepoetin alfa and
dephosphorylation of janus kinase (JAK-2), acting as a negative regulator CERA. Other modifications to the EPO molecule, such as the production of
of EPO intracellular signal transduction. The potential importance of this fusion proteins, are being explored, as is the potential for EPO gene therapy.
molecule in mediating responsiveness to EPO therapy was studied in The concept that smaller molecules such as peptides or even non-peptides
CD34+ cells derived from haemodialysis patients responding poorly to may be able to bind to and activate the EPO receptor is also being explored,
EPO.
27
As with the GATA inhibitors, HCP inhibitors have not yet been and the first such molecule (Hematide) is already in phase III of its clinical
tested in humans and it is not clear whether they will have a role in the development programme. Other strategies attempting to create orally active
management of CKD anaemia. However, they could potentially be used agents, such as inhibition of prolyl hydroxylase, GATA or haemopoietic cell
as adjuvant therapy to enhance the response to other ESAs, or even to phosphatase, remain in the laboratory, but may yet translate into future
enhance the patient’s own endogenous EPO. therapeutic agents for the management of CKD anaemia. ■
Erythropoietin Gene Therapy Disclosure
With increasing concern that high doses of erythropoietic products may Iain C Macdougall has received consulting fees, lecture fees and grant
be harmful, the ability to generate lower but more continuous levels of support from Amgen, Ortho Biotech, Roche, Shire and Affymax.
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30 EUROPEAN RENAL DISEASE 2007
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