Amelioration of β^(654)-thalassemia in mouse model with the knockdown of aberrantly spliced β-globin mRNA  

作　　者：Shuyang Xie Wei Li Zhaorui Ren Jingzhi Zhang Xinbin Guo Shu Wang Shuzhen Huang Fanyi Zeng Yi-Tao Zeng 

机构地区：[1]Shanghai Institute of Medical Genetics, Shanghai Children＇s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China.

出　　处：《Journal of Genetics and Genomics》2008年第10期595-601,共7页遗传学报（英文版）

基　　金：the National Basic Research Program of China (973 Program) (No 2004CB518806);the National High-tech R&D Program (863 Program) (No 2007AA021206);the National Natural Science Foundation of China (No 30571777);the Chinese National and Shanghai Leading Academic Disci-pline Project (No B204)

摘　　要：Large amounts of aberrantly spliced mRNA from the β^654 allele was present in erythroid cells, which might impair the erythropoiesis. A therapeutic strategy for β-thalassemia was explored by knocking down the aberrantly spliced mRNA of β-globin. Lentiviral vector with siRNA fragment targets on the specific portion of β^654-globin aberrantly spliced pre-mRNA was constructed. In HeLa β^654 cells, the siRNA vector could reduce approximately 60% of aberrantly spliced mRNA, which was assessed by RT-PCR and qRT-PCR. Furthermore, a disease model of β^654 thalassemia mice with lentiviral-mediated siRNA was produced by subzonal injection （named Hβi-Hbb^th-4/Hbb^＋ transgenic mice）. Our results showed that the hemotological parameters were improved in Hβi-Hbb^th-4/Hbb^＋ transgenic mice. This study provides a potential way for β^654-thalassemia therapy by knocking down the aberrantly spliced β-globin mRNA, whilst supporting that the aberrantly spliced β-globin mRNA may aggravate the disease.Large amounts of aberrantly spliced mRNA from the β^654 allele was present in erythroid cells, which might impair the erythropoiesis. A therapeutic strategy for β-thalassemia was explored by knocking down the aberrantly spliced mRNA of β-globin. Lentiviral vector with siRNA fragment targets on the specific portion of β^654-globin aberrantly spliced pre-mRNA was constructed. In HeLa β^654 cells, the siRNA vector could reduce approximately 60% of aberrantly spliced mRNA, which was assessed by RT-PCR and qRT-PCR. Furthermore, a disease model of β^654 thalassemia mice with lentiviral-mediated siRNA was produced by subzonal injection （named Hβi-Hbb^th-4/Hbb^＋ transgenic mice）. Our results showed that the hemotological parameters were improved in Hβi-Hbb^th-4/Hbb^＋ transgenic mice. This study provides a potential way for β^654-thalassemia therapy by knocking down the aberrantly spliced β-globin mRNA, whilst supporting that the aberrantly spliced β-globin mRNA may aggravate the disease.

关 键 词：Β-THALASSEMIA small interfering RNA （siRNA） HEMOGLOBIN 

分 类 号：R556[医药卫生—血液循环系统疾病]