Journal
HUMAN MOLECULAR GENETICS
Volume 16, Issue 21, Pages 2616-2625Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddm218
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The beta- thalassemia is associated with abnormality in beta- globin gene, leading to imbalanced synthesis of alpha-/beta-globin chains. Consequently, the excessive free alpha-globin chains precipitate to the erythrocyte membrane, resulting in hemolytic anemia. We have explored post-transcriptional strategies aiming at alpha-globin reduction and beta-globin enrichment on beta(654) (Hbb(th-4)/Hbb(+)) mouse, carrying a human splicing-deficient beta-globin allele (Hbb(th-4)). Lentiviral vectors of short hairpin RNA (shRNA) targeting alpha-globin and/or antisense RNA facilitating beta-globin correct splicing were microinjected into beta(654) single-cell embryos. Three transgenic strains were generated, as alpha(1)-Hbb(th-4)/Hbb(+)(shRNA), beta(a)-Hbb(th- 4)/Hbb(+)(antisense) and alpha(1)beta(a)-Hbb(th-4)/Hbb(+) (both shRNA and antisense). Without notable abnormalities, all the founders and their offsprings showed sustained amelioration of hematologic parameters, ineffective erythropoiesis and extramedullary hematopoiesis. Augmented effects appeared in alpha(1)beta(a)-Hbb(th-4)/Hbb(+), which correlated with a better-balanced alpha-/beta- globin mRNA level. Among the transgenic mice integrated with shRNA and antisense RNA, one homozygous mouse (Hbb(th-4)/Hbb(th-4)) had been viable, and the 3-week survival rate for heterozygotes (Hbb(th- 4)/Hbb(+)) was 97%, compared with 45.4% for untreated. Our data have demonstrated the feasibility of techniques for beta-thalassemia therapy by balancing the synthesis of alpha-/beta-globin chains.
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