More than four decades after the mutation that causes sickle cell disease was first identified, researchers have finally taken a major step toward treating the blood disorder. According to a report published today in the journal Science, a novel gene therapy method prevents the characteristic deformation, or sickling, of red blood cells in mice.

Sickle cell diseasewhich occurs most frequently in people of African, Indian, Middle Eastern and Mediterranean descentis an inherited disorder caused by a mutation in the beta globin gene that causes people to manufacture abnormal hemoglobin. As a result, red blood cells, which normally appear doughnut-shaped, take on a sickle-like form that can stick in blood vessels and block blood flow. To address this problem, Robert Pawliuk of the Massachusetts Institute of Technology and colleagues created an anti-sickling variant of the beta globin gene that, when introduced to bone marrow via so-called lentiviral vectors, inserts itself into the stem cells that produce red blood cells.

Their tactic proved highly successful: 10 months after transplantation, up to 99 percent of all red blood cells in the diseased mice expressed the new gene. Sickled cells were thus greatly reduced or eliminated altogether. The images at the right show red blood cells in mice with a model of sickle cell disease that did not receive the anti-sickling gene (top) and those that did receive it (bottom). Furthermore, the gene therapy corrected other problems associated with the diseaseincluding spleen enlargement and a urine concentration defect.

The results represent a rare success. "Usually when a copy of a new gene lands in the genome this way, it is strongly influenced by its surrounding, and often gets silenced," notes team member Philippe Leboulch, also at MIT. "But when the expression level is very high, and spread evenly through the cells, as it is in the case with lentiviral vectors, the gene can do its work." Still, the researchers have considerable work ahead of them before such a treatment can be evaluated in human clinical trials. Among other things, they hope to find a way to introduce the gene therapy without first irradiating the existing bone marrow