β-Thalassemia (β-Thal) is a group of life-threatening blood disorders caused by 
either point mutations or deletions of nucleotides in β-globin gene (HBB). It is 
estimated that 4.5% of the population in the world carry β-Thal mutants (1), 
posing a persistent threat to public health. The generation of patient-specific 
induced pluripotent stem cells (iPSCs) and subsequent correction of the 
disease-causing mutations offer an ideal therapeutic solution to this problem. 
However, homologous recombination-based gene correction in human iPSCs remains 
largely inefficient. Here, we describe a robust process combining efficient 
generation of integration-free β-Thal iPSCs from the cells of patients and 
transcription activator-like effector nuclease (TALEN)-based universal 
correction of HBB mutations in situ. We generated integration-free and 
gene-corrected iPSC lines from two patients carrying different types of 
homozygous mutations and showed that these iPSCs are pluripotent and have normal 
karyotype. We showed that the correction process did not generate TALEN-induced 
off targeting mutations by sequencing. More importantly, the gene-corrected 
β-Thal iPS cell lines from each patient can be induced to differentiate into 
hematopoietic progenitor cells and then further to erythroblasts expressing 
normal β-globin. Our studies provide an efficient and universal strategy to 
correct different types of β-globin mutations in β-Thal iPSCs for disease 
modeling and applications.