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