Blood, 15 March 2002, Vol. 99, No. 6, pp. 1883-1884
Thalassemia gene therapy looks good at one year
In 2000, May and colleagues reported that a lentivirus
containing a human 
-globin gene and sequences from the
locus control region (LCR) could be efficiently transferred into
hematopoietic stem cells of mice with -thalassemia minor. In
recipient red cells, the human -globin mRNA and protein were present
at levels of 13% of endogenous -globin per vector copy, and
the red cell indices were significantly improved. This was an
important advance for the field, demonstrating that lentivirus vectors
could overcome the instability of globin retroviral vectors and that
high levels of globin gene expression could be achieved. Recent work at
the Massachusetts Institute of Technology, St Jude, and the University of Washington has confirmed the soundness of the lentivirus approach.
These results were only the beginning. Many researchers have found that
transgene expression from viral vectors can be si-lenced over time. It
was also not clear whether the secondary consequences of thalassemia
could be corrected by the amount of human -globin produced. In this
issue May and colleagues (page 1902) have laid these concerns to rest.
Irradiated thal/+ recipients received transplants of thal/+ marrow
transduced with either control or globin lentivirus vectors. The
recipients were observed for 40 weeks after transplantation, nearly
half the life span of a mouse. Human -globin mRNA and protein levels
were consistently 16% of endogenous -globin throughout the study
period, indicating that no silencing had occurred. In addition, a
careful study of extramedullary hematopoiesis in the spleen and iron
accumulation in the liver demonstrated that transfer of the human
-globin gene restored normal hematopoiesis in the spleen
and prevented the accumulation of iron in the liver. These are
important findings that demonstrate the feasibility of gene therapy for
treating hemoglobinopathies.
Clinical gene therapy of thalassemia has more challenges for May and
colleagues. Can gene therapy cure the more severe forms of thalassemia?
Are HIV-based lentivirus vectors safe for clinical gene therapy?
Preliminary results are promising, but more studies such as this one
will be needed to fully answer these questions.
David M. Bodine
National Human Genome Research Institute
