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Beta‐thalassemia is one of the most common recessive genetic diseases, caused by mutations in the  HBB  gene. Over 200 different types of mutations in the  HBB  gene containing three exons have been identified in patients with β‐thalassemia (β‐thal) whereas a homozygous mutation in exon 1 causes sickle cell disease (SCD). Novel therapeutic strategies to permanently correct the  HBB  mutation in stem cells that are able to expand and differentiate into erythrocytes producing corrected HBB proteins are highly desirable. Genome editing aided by CRISPR/Cas9 and other site‐specific engineered nucleases offers promise to precisely correct a genetic mutation in the native genome without alterations in other parts of the human genome. Although making a sequence‐specific nuclease to enhance correction of a specific  HBB  mutation by homology‐directed repair (HDR) is becoming straightforward, targeting various  HBB  mutations of β‐thal is still challenging because individual guide RNA as well as a donor DNA template for HDR of each type of  HBB  gene mutation have to be selected and validated. Using human induced pluripotent stem cells (iPSCs) from two β‐thal patients with different  HBB  gene mutations, we devised and tested a universal strategy to achieve targeted insertion of the  HBB  cDNA in exon 1 of  HBB  gene using Cas9 and two validated guide RNAs. We observed that HBB protein production was restored in erythrocytes derived from iPSCs of two patients. This strategy of restoring functional  HBB  gene expression will be able to correct most types of  HBB  gene mutations in β‐thal and SCD.  Stem Cells Translational Medicine   2018;7:87–97

A Universal Approach to Correct Various HBB Gene Mutations in Human Stem Cells for Gene Therapy of Beta‐Thalassemia and Sickle Cell Disease