Murine Gene Therapy Corrects Symptoms of Sickle Cell Disease

The Faculty of 1000 is a Web-based literature awareness tool published by BioMed Central. It provides a continuously updated insider's guide to the most important peer-reviewed papers within a range of research fields, based on the recommendations of a faculty of more than 1,400 leading researchers. Each issue, The Scientist publishes a list of the 10 top-rated papers from a specific subject area, as well as a short review of one or more of the listed papers. We also publish a selection of comments on interesting recent papers from the Faculty of 1000's output. For more information visit www.facultyof1000.com. Caused by a simple gene mutation that misshapes red blood cells and renders them ineffective, sickle cell disease (SCD) seemed to provide scientists with a straightforward target for gene therapy. But since the first SCD gene therapy experiment in 1979, researchers continue to struggle. It wasn't until late 2001, in a paper listed in the Faculty of 1000's Top 10 Genomics list for Feb. 15, that scientists corrected the murine symptoms of this chronic, inherited, and often painful disorder.1 F1000 Top 10All of Biology 1. A.-C. Gavin et al., "Functional organization of the yeast proteome by systematic analysis of protein complexes," Nature, 415:141-7, Jan. 10 2002. 2. S. El-Din El-Assal et al., "A QTL for flowering time in Arabidopsis reveals a novel allele of CRY2," Nature Genetics, 29:435-40, December 2001. 3. C.L. Peichel et al., "The genetic architecture of divergence between threespine stickleback species," Nature, 414:901-5, Dec. 20, 2001. 4. J.N. Maloof et al., "Natural variation in light sensitivity of Arabidopsis," Nature Genetics, 29:441-6, December 2001. 5. D. Bourc'his et al., "Dnmt3L and the establishment of maternal genomic imprints, "Science, 294:2536-9, Dec. 21, 2001. 6. B.P. Berman et al., "Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome," Proceedings of the National Academy of Sciences, 99:757-62, Jan. 22, 2002. 7. V. Brown et al., "Microarray identification of FMRP-associated brain mRNA and altered mRNA translational profiles in fragile X syndrome," Cell, 107:477-87, Nov. 16, 2001. 8. W. Jin et al., "The contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster," Nature Genetics, 29:389-95, December 2001. 9. R. Pawliuk et al., "Correction of sickle cell disease in transgenic mouse models by gene therapy," Science, 294:2368-71, Dec. 14, 2001. 10. K. Dennis et al., "Lsh, a member of the SNF2 family, is required for genome-wide methylation," Genes & Development, 15:2940-4, Nov. 15, 2001.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. Jennifer Fisher Wilson (jfwilson@snip.net) is a contributing editor. References 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.

Murine Gene Therapy Corrects Symptoms of Sickle Cell Disease

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