Chang Judy C, Ye Lin, Kan Yuet Wai
Department of Laboratory Medicine, Cardiovascular Research Institute and Center of Human Genetics, University of California, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2006 Jan 24;103(4):1036-40. doi: 10.1073/pnas.0510177103. Epub 2006 Jan 11.
Sickle cell anemia is one of the most common genetic diseases worldwide. Patients often suffer from anemia, painful crises, infections, strokes, and cardiopulmonary complications. Although current management has improved the quality of life and survival of patients, cure can be achieved only with bone marrow transplantation when histocompatible donors are available. The ES cell technology suggests that a therapeutic cloning approach may be feasible for treatment of this disease. Using a transgenic/knockout sickle cell anemia mouse model, which harbors 240 kb of human DNA sequences containing the beta(S)-globin gene, we prepared ES cells from blastocysts that had the sickle cells anemia genotype and carried out homologous recombination with DNA constructs that contained the beta(A)-globin gene. We obtained ES cells in which the beta(S) was corrected to the beta(A) sequence. Hematopoietic cells differentiated from these ES cells produced both hemoglobin A and hemoglobin S. This approach can be applied to human ES cells to correct the sickle mutation as well as beta-thalassemia mutations.
镰状细胞贫血是全球最常见的遗传疾病之一。患者常患有贫血、疼痛性危象、感染、中风和心肺并发症。尽管目前的治疗方法改善了患者的生活质量和生存率，但只有在有组织相容性供体时通过骨髓移植才能实现治愈。胚胎干细胞技术表明，治疗性克隆方法可能对治疗这种疾病可行。利用转基因/基因敲除镰状细胞贫血小鼠模型（该模型含有240 kb包含β(S)-珠蛋白基因的人类DNA序列），我们从具有镰状细胞贫血基因型的囊胚中制备了胚胎干细胞，并与含有β(A)-珠蛋白基因的DNA构建体进行同源重组。我们获得了β(S)被校正为β(A)序列的胚胎干细胞。从这些胚胎干细胞分化而来的造血细胞产生了血红蛋白A和血红蛋白S。这种方法可应用于人类胚胎干细胞以纠正镰状细胞突变以及β地中海贫血突变。
