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The successful pathway proved far more complex and challenging than initially imagined, says lead investigator gene therapist Philippe Leboulch, of the Massachusetts Institute of Technology and Harvard University. "Everybody thought it would be the first genetic disorder cured by gene therapy, that it would be simple, but it turned out to be completely different. It was a real challenge," says Leboulch, who has worked with SCD for more than 10 years.
Two key factors made SCD a promising candidate for gene therapy research. First, the sickle cell mutation is a single point alteration in the human bA-globin gene, which causes the formation of an abnormal hemoglobin. Second, scientists could isolate bone marrow stem cells relatively easily and introduce potential anti-sickling genes ex vivo. But success required overcoming difficult problems such as delivering a normal gene to the body, manipulating the gene for long-term expression and a high level of effectiveness, and creating mouse models.
A turning point came from Michel Sadelain's lab at Memorial Sloan-Kettering Cancer Center in New York. In 2000,2 Sadelain detailed the first successful use of an HIV-based lentiviral vector for the long-term correction of the blood disorder b-thalassemia, in which the body makes too little hemoglobin. Murine models treated in Sadelain's lab continue to show correction of the disorder, he notes.
In 2001, LeBoulch's team used an HIV-based vector to transplant healthy stem cells carrying a specially manipulated bA-globin gene called gemisch into murine models. The gene therapy resulted in almost 100% expression of functioning red blood cells with anti-sickling globin and corrected all SCD symptoms. The mice have maintained this rate for more than a year, Leboulch reports.
While advances from the Sadelain and Leboulch labs are important to treating thalassemia and SCD, they also benefit the general biological and medical disciplines. "The work provides models for addressing the challenge of how to put a gene into a stem cell and, once doing so, control its expression and function in the body," says Sadelain.
Human trials are not yet ready to begin because further safety tests are needed on the HIV-based vector, notes Leboulch. Investigators are also searching for better treatments than chemotherapy and radiation to remove unhealthy stem cells from a patient's bone marrow. "We have to be cautious and reasonable about our expectations," Leboulch says, noting that interest in curing SCD and thalassemia is particularly high. He expects the first human trials to launch in about three years.
1. R. Pawliuk et al., "Correction of sickle cell disease in transgenic mouse models by gene therapy," Science, 294:2368-71, Dec. 14, 2001.
2. C. May et al., "Therapeutic haemoglobin synthesis in beta-thalassaemic mice expressing lentivirus-encoded human beta-globin," Nature, 406:82-6, 2000.