Using a harmless virus to insert a corrective gene into mouse blood cells, scientists at St. Jude Children's Research Hospital have alleviated sickle cell disease pathology.

In their studies, published Thursday in the journal Molecular Therapy, the researchers found that the treated mice showed essentially no difference from normal mice. Although they caution that applying the gene therapy to humans faces significant technical obstacles, they believe the new therapy will become an important treatment for the disease.

Sickle cell disease, which affects millions of people worldwide, arises because of a tiny genetic defect in the gene for beta-globin, a protein component of hemoglobin. This defect causes hemoglobin-containing red blood cells to tend to deform, clump and break apart. The resulting clogged blood vessels can lead to cognitive dysfunction by causing small strokes in the brain and cause damage to kidneys, liver, spleen and lungs.

The only permanent cure for the disease is a bone marrow transplant to give recipients blood-forming cells that will form normal beta-globin. However, such transplants are rare because of the lack of compatible donors.

Researchers have long known that symptoms of the disease could be alleviated by persistence in the blood of an immature fetal form of hemoglobin in red blood cells. This immature hemoglobin, which usually disappears after birth, does not contain beta-globin, but another form called gamma-globin. St. Jude researchers had found that treating patients with the drug hydroxyurea encourages the formation of fetal hemoglobin and alleviates disease symptoms.

"While this is a very useful treatment for the disease, our studies indicated that it might be possible to cure the disorder if we could use gene transfer to permanently increase fetal hemoglobin levels," said lead researcher Derek Persons.

In the experiments, the research team used a strain of mouse with basically the same genetic defect and symptoms as humans with sickle cell disease. They developed a technique to insert the gene for gamma-globin into mouse blood-forming cells with a harmless viral carrier.

They found that months after they introduced the altered blood-forming cells, the mice continued to produce gamma-globin in their red blood cells. "The mice showed no anemia, and their organ function was essentially normal."

"The results demonstrate for the first time that it is possible to correct sickle cell disease with genetic therapy to produce fetal hemoglobin," said Persons. "We think that increased fetal hemoglobin expression in patients will be well tolerated and the immune system would not reject the hemoglobin, in comparison to other approaches."

While Persons believes that the mouse experiments will lead to treatments in humans, he cautioned that technical barriers still need to be overcome. "It is far easier to achieve high levels of gene insertion into mouse cells than into human cells."

His laboratory is currently working with other animal and human cells to develop methods with high enough gene insertion rates to make the gene therapy clinically useful.