Therapeutic haemoglobin synthesis in -thalassaemic mice

Rcjohnsen rcjohnsen at
Sat Jul 8 12:27:28 EST 2000

Nature 406, 82 - 86 (2000) © Macmillan Publishers Ltd. 
Therapeutic haemoglobin synthesis in -thalassaemic mice expressing
lentivirus-encoded human -globin
The stable introduction of a functional -globin gene in haematopoietic stem
cells could be a powerful approach to treat -thalassaemia and sickle-cell
disease. Genetic approaches aiming to increase normal -globin expression in the
progeny of autologous haematopoietic stem cells might circumvent the
limitations and risks of allogeneic cell transplants. However, low-level
expression, position effects and transcriptional silencing hampered the
effectiveness of viral transduction of the human -globin gene when it was
linked to minimal regulatory sequences. Here we show that the use of
recombinant lentiviruses enables efficient transfer and faithful integration of
the human -globin gene together with large segments of its locus control
region. In long-term recipients of unselected transduced bone marrow cells,
tetramers of two murine -globin and two human A-globin molecules account for up
to 13% of total haemoglobin in mature red cells of normal mice. In
-thalassaemic heterozygous mice higher percentages are obtained (17% to 24%),
which are sufficient to ameliorate anaemia and red cell morphology. Such levels
should be of therapeutic benefit in patients with severe defects in haemoglobin


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