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Gene therapy for beta-thalassemia successful in mice
By Bijal P. Trivedi

The gene for beta-thalassemia is more frequent in Greeks and Italians.

More than 200 million people around the world suffer from a group of inherited blood disorders called thalassemias, which, in severe forms, are fatal. These diseases are caused by the faulty production of hemoglobin, the protein in a red blood cell that transports oxygen to the tissues in the body. Now, a research team based at the Memorial Sloan-Kettering Cancer Center in New York has used a gene to bring one form of the disease, beta-thalassemia, under control in mice. The result offers hope that the same approach may work in people.

Hemoglobin is made up of four pieces: two beta-globin and two alpha-globin proteins. In beta-thalassemia, the problem is the production of beta-globin parts. When only one copy of the beta-globin gene is damaged, the result is a mild anemia that does not require treatment. But when both copies are damaged, children often die at a young age. Severe beta-thalassemia is treated with regular blood transfusions, and, in some cases, a bone marrow transplant. But bone marrow transplants are not available to everyone, and are risky because of complications with the immune system. Transfusions can cause a dangerous build-up of iron in the heart muscle.

Both transfusions and transplants have risks

"That is what makes a genetic approach so attractive," says Michel Sadelain, a gene therapy researcher at the Memorial Sloan-Kettering Cancer Center. If a patient's own bone marrow cells are removed and have a healthy beta-globin gene inserted, the cells are returned to the patient and normal hemoglobin should be produced without any complications with the immune system, he says. The team tested this approach in mice. The results are presented in a recent issue of Nature.

Sadelain's group packaged the healthy beta-globin gene and an adjacent area of the DNA, which controls when and where the gene is turned on, into a virus. The virus was then mixed with bone marrow cells that had been removed from mice with beta-thalassemia. When the virus injects the DNA into the cell, the gene joins the rest of the DNA and becomes part of the cell's chromosomes. When this happens to bone marrow stem cells, the precursors for all the blood cells in the body, the healthy beta-globin gene will be passed to all future generations of blood cells, says Sadelain.

Fifteen weeks after the altered bone marrow cells were placed back into the mouse, hemoglobin levels had risen to 12-13 grams per deciliter (g/dL) compared to 8-9 g/dl in untreated mice with an intermediate form of beta-thalassemia. Healthy mice have hemoglobin levels in the range of 15 g/dl.

The production of normal hemoglobin from the newly introduced gene corrected the sickly appearance of the red blood cells. Normal red blood cells are packed with hemoglobin and are bright, plump, and round with a dimple in the center. "The red blood cells from a person or mouse with beta-thalassemia have very low levels of hemoglobin. The cells are pale and fragile and have bizarre shapes like tear drops and spikes, which are easy to recognize under the microscope," says Sadelain.

Curative levels of hemoglobin were produced in mice

While other groups have tried to insert a healthy beta-globin gene into mice, none have succeeded in getting curative levels of the hemoglobin protein. Until now, it has also been difficult to restrict the production to only the red blood cells, according to Charles Peterson, Director of the Blood Diseases Program at the National Heart, Lung, and Blood Institute in Bethesda, Maryland. High levels of hemoglobin are toxic to other cell types.

"Sadelain's group gets 17 to 24 percent production of the healthy beta-globin protein, which is excellent, because with this level you fix most of what goes wrong," says Peterson.

The work also holds promise for sickle cell anemia, which also results from two copies of a faulty beta-globin gene, and which might be treated the same way, says Peterson. About one in 12 people of African descent worldwide has a single copy of the sickle cell gene, while one in 400 has the disease.

First discovered in people living around the Mediterranean Sea, Thalassemia gets its name from the Greek "thalassa" meaning sea and "emia" meaning blood. The disease is particularly prevalent among Greeks and Italians, Southeast Asians and Africans. The sickle cell and beta-thalassemia genes are thought to have persisted in these populations because having a copy of either gene protects against malaria.

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May, C. et al. Therapeutic haemoglobin synthesis in b-thalassaemic mice expressing lentivirus-encoded human b-globin. Nature 406, 82-86 (July 6, 2000).

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