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Small Study of Gene Editing to Treat Sickle Cell Disease

An early-stage study of a CRISPR-Cas9-based treatment coaxes cells to produce fetal hemoglobin and decreases painful symptoms of sickle cell disease, researchers report in a Novartis Pharmaceuticals-sponsored study appearing in the New England Journal of Medicine. Sickle cell disease is caused by mutations in the HBB gene, which encodes a subunit of adult hemoglobin, and those mutations lead hemoglobin to sickle and accumulate, causing pain. But reactivating fetal hemoglobin — encoded by HBG1 and HBG2 — could treat the condition. Through a CRISPR-Cas9 screen testing six dozen guide RNAs targeting the HBG1 and HBG2 promoters, the researchers homed in on one that led to the highest proportion of fetal hemoglobin. In a subsequent Phase I/II study, the researchers assessed the safety and adverse-effect profile of OTQ923, an autologous, ex vivo CRISPR-Cas9 edited, CD34+ hematopoietic stem-cell product using that guide RNA, in three patients with severe sickle cell disease. Trial participants, they report, had higher levels of fetal hemoglobin and experienced fewer symptoms of sickle cell disease following treatment. "The biggest take-home message is that there are now more potentially curative therapies for sickle cell disease than ever before that lie outside of using someone else's stem cells, which can bring a host of other complications," senior author James LaBelle from UChicago Medicine and Comer Children's Hospital says in a statement.