Mouse Model of Sickle Cell Anemia Successfully Treated by Gene Therapy

Researchers have used an advanced gene therapy technique to cure sickle cell anemia in a mouse model of the disease.

The sickle cell mutation is caused by a single nucleotide effecting a change in the beta-globin gene, resulting in the substitution of valine for glutamic acid as the sixth amino acid of beta-globin. This mutation greatly reduces the circulatory survival of the red blood cells containing sickle cell hemoglobin S. This causes anemia, and the red cells' abnormal rigidity contributes to painful obstruction of small blood vessels.

When fetal hemoglobin production is switched off after birth, normal children begin producing adult hemoglobin (HbA.) But children with sickle-cell disease instead begin producing a defective form of hemoglobin called hemoglobin S. This variety of hemoglobin aggregates, forming filaments and so causes red blood cells to change their shape from round to sickle-shaped, which have a greater tendency to stack on top of one another and crowd blood vessels. These invariably lead to so-called painful vaso-occlusive episodes, which are a hallmark of the disease. It has been known for many years that these symptoms of sickle cell disease could be alleviated by persistence of the immature fetal form of hemoglobin in the red blood cells.

Hydroxyurea, used also as an anti-cancer drug, has been shown to be a viable treatment for sickle cell anemia, as it promotes the production of fetal hemoglobin while inhibiting the formation of sickle cells due to hemoglobin S polymerization.

In the current study investigators at St. Jude Children's Research Hospital (Memphis, TN, USA sought to transplant the gene for human fetal hemoglobin into a mouse model of sickle cell anemia in order to mimic the benefits of hydroxyurea on a permanent basis.

They extracted bone marrow cells from mice with sickle cell disorder and infected them with a lentivirus vector carrying the gene for fetal hemoglobin along with a DNA promoter region. The cells were then returned to the animals from which they had been taken.

Results published in the December 2, 2008, online issue of the journal Molecular Therapy revealed that the treated mice produced fetal hemoglobin, and that this production continued for many months. All symptoms of sickle cell disease in these animals disappeared. Furthermore, transplantation of bone marrow from these mice into a new generation of sickle cell animals triggered production of fetal hemoglobin and cure of the disease in those animals.

"When we examined the treated mice, we could detect little, if any, disease using our methods,” said senior author Dr. Derek Persons, assistant professor of hematology at St. Jude Children's Research Hospital. "The mice showed no anemia, and their organ function was essentially normal. We are very encouraged by our results, as they demonstrate for the first time that it is possible to correct sickle cell disease with genetic therapy to produce fetal hemoglobin. 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.”

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