High-level correction of the sickle mutation amplified in vivo during erythroid differentiation
Mark A DeWitt,
Stacia K Wyman,
Jonathan T. Vu,
Shirley J Shao,
Zulema G. Romero,
Garrett R. Rettig,
Patrick J. Lau,
Mark A Behlke,
Donald B Kohn,
Mark C Walters,
Jacob E. Corn,
David I.K. Martin
Posted 03 Oct 2018
bioRxiv DOI: 10.1101/432716
Posted 03 Oct 2018
Sickle Cell Disease (SCD), one of the world's most common genetic disorders, causes anemia and progressive multiorgan damage that typically shortens lifespan by decades; currently there is no broadly applicable curative therapy. Here we show that Cas9 RNP-mediated gene editing with an ssDNA oligonucleotide donor yields more than 20% correction of the sickle mutation in long-term engrafting human HSCs. Using RNA-seq, we further find that in vivo erythroid differentiation markedly enriches for cells carrying corrected β-globin alleles. Adoption of a high-fidelity Cas9 variant demonstrates that this approach can yield efficient editing with almost no off-target events. These findings indicate that the sickle mutation can be corrected in human HSCs at levels that are likely to be curative if translated into a therapy.
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