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October 2000
Vol. 3, No. 8, p. 11.

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Gene therapy in thalassemic mice

red blood cellsUsing HIV as a vector, researchers in New York have genetically engineered mouse red blood cells to manufacture an abundant supply of human hemoglobin. If the technique proves safe and effective in humans, it could provide a treatment for diseases such as sickle cell anemia and β-thalassemia, in which β-globin—one of the two proteins that compose hemoglobin—is defective or inadequately produced. Scientists hope to treat both disorders with gene therapy by using a virus to smuggle a functional copy of the gene into bone marrow stem cells, and then infusing these cells into patients.

But previous attempts to engineer mouse cells to make significant quantities of human hemoblogin have foundered on two problems—hemoglobin production was often low, and it dwindled over time—says geneticist Michel Sadelain of the Memorial Sloan-Kettering Cancer Center (New York).

To correct these problems, Sadelain and colleagues made two changes to the standard technique. First, instead of using an oncovirus to ferry the -globin gene into the target cells, they used a version of HIV stripped of most of its genes. This was preferable because HIV usually delivers intact sequences, whereas oncovirus-mediated genes are prone to rearrangement.

Second, the team included a larger portion of the locus control region (LCR) that regulates gene expression. Sadelain and colleagues reasoned that longer LCR sequences would give the target cells more control over gene expression and reduce variability in protein production.

After infecting mouse bone marrow cells with altered virus, the researchers transplanted the cells into mice with -thalassemia or whose bone marrow had been destroyed with radiation. In the irradiated mice, human gene expression remained high (10–20% of all -globin transcripts) throughout the 24 weeks of the study (Nature 2000, 406, 82–86). Similarly, 17–24% of the β-globin in the thalassemic mice came from the human gene.

Safety remains the big hurdle for the technique. Although animal trials are reassuring, Sadelain expects extra scrutiny in the move to humans. “It remains a challenge for the future of this vector to show it is as safe as other retroviruses,” he says.


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