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Study results show promise for development of gene therapy to treat blood diseases


Researchers have developed a promising new approach for gene therapy of inherited blood disorders that may help overcome therapeutically limiting human stem cell gene transfer efficiency. This method would be applicable to patients with beta-thalassemia, a potentially life-threatening blood disease, as well as other genetic blood disorders, according to a study published in the July 15th issue of Blood. By transplanting beta-thalassemic mice with stem cells treated with MGMT (methylguanine methyltransferase), a drug-resistance gene, researchers were able to subsequently give a chemotherapy drug to the mice, which specifically increased the normal, or globin-expressing cells, to levels that diminished, or in some cases, cured the disease. The transplanted donor stem cells genetically reversed the beta-thalassemia in the mice because the drug-resistant cells assumed production of normal red blood cells in the bone marrow.

"Our finding gives us hope that we might one day be able to help patients with hemoglobin diseases generate healthy blood cells in their own bodies," said Derek Persons, MD, assistant member in the St. Jude Department of Hematology/Oncology, Memphis, TN, and lead author of the paper. "The technique we pioneered will allow us to enrich the population of cells carrying the normal gene by eliminating competing, defective cells, without using radiation or intensive chemotherapy."

Researchers in the study used an oncoretrovirus to transfer MGMT into normal bone marrow cells. The treated cells were then transplanted into beta-thalassemic mice previously given non-myeloablative (non-life-threatening) pre-transplant conditioning with the cytotoxic agents temozolomide (TMZ) and O6-benzylguanine (BG). The transplanted mice were randomly assigned to receive either drug treatment with TMZ/BG (two five-day courses, five weeks apart, beginning seven weeks after transplant) or no treatment.

Researchers achieved successful in vivo (in the body) selection in 66 percent (19 of 29) of the mice. Following treatment with TMZ/BG, the treated mice showed persistent improvement of their blood, suggesting that the modified stem cells assumed the production of red blood cells after the treatment eliminated the defective stem cells. A majority of the mice also showed resolution of anemia with nearly complete, stable conversion to the donor red blood cells.

"Currently, we are unable to transplant an adequate number of genetically altered bone marrow cells into humans to result in successful treatment of these diseases," said Dr. Persons. "We believe that further animal studies will ultimately determine the feasibility of using the MGMT selection process as a treatment."

Beta-thalassemia is an inherited blood disorder that occurs when a person’s red blood cells do not produce enough beta globin protein to result in adequate levels of hemoglobin (the oxygen-carrying component of the red blood cells). The red cells need to produce enough of both the beta globin and alpha globin proteins to ensure that the red blood cells form properly and are able to carry sufficient oxygen. If the body is unable to produce adequate amounts, the result will be anemia that begins in early childhood and lasts throughout a patient’s life. Children with untreated beta-thalassemia may die in the first decade of life if they do not receive adequate treatment.

The most common treatment for beta-thalassemia is red blood cell transfusions, which provide the patient with a temporary supply of healthy cells that function normally and supply the body with the needed oxygen. Patients with a major form of thalassemia receive red blood cell transfusions every two to three weeks, which translates to as many as 52 pints of blood a year. However, the high number of red blood cell transfusions these patients receive can lead to iron overload which, if left untreated, may result in early death from organ failure. Alternatively, some patients may undergo bone marrow transplantation with cells from a matched normal donor. However, this treatment is not available for all patients and entails significant risk. Therefore, new treatment approaches are needed.

"The use of gene-modified stem cells to correct inherited blood diseases has been a very attractive idea, but achieving this goal has been quite difficult. Modifying large numbers of adult hematopoietic stem cells is very difficult, and expanding a small number of successfully modified stem cells in the laboratory has proven even harder. This careful study provides an important example of how basic hematology research can lead to solutions to the problems that remain before gene-modified stem cells can be safely and successfully used in medical therapy," notes Stephen Emerson, MD, PhD, Francis C. Wood Professor in Medicine and Chief of Hematology/Oncology at the University of Pennsylvania.

According to the Cooley’s Anemia Foundation, it is estimated that more than two million people in the United States carry the genetic trait for thalassemia. For this reason, the National Institutes of Health recommend that all US citizens should be tested for the thalassemia trait.

Blood, the Journal of the American Society of Hematology, is the most cited peer-reviewed publication in the field. All articles undergo rigorous peer review and are selected for publication on the basis of the originality and quality of the work described. As a special service to researchers and clinicians, accepted papers are made available online about three months ahead of print as "First Edition Papers." Blood is issued to Society members and other subscribers twice per month, available in print and online at

Aimee Frank | EurekAlert!
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