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Dana-Farber Researchers Use Gene Editing to Short-Circuit Sickle Cell Disease

NEW YORK (GenomeWeb) – Scientists have developed a gene editing strategy that could help treat sickle cell disease by short-circuiting the mutated hemoglobin causing the disease. 

"We've now targeted the modifier of the modifier of a disease-causing gene," Stuart Orkin, chairman of pediatric oncology at Dana-Farber Cancer Institute and associate chief of hematology/oncology at Boston Children's Hospital, said in a statement. "It's a very different approach to treating disease."

Using CRISPR/Cas9 gene editing tools to systematically excise stretches of a promoter region of the enhancer gene BCL11A — which selects the type of hemoglobin that blood cells create — the researchers found an edit that inactivated BCL11A in human blood stem cells. The cut leads cells to increase levels of fetal hemoglobin, resulting in a milder form of sickle cell disease. 

"Our goal was to break the enhancer, rather than fix the hemoglobin mutation" Orkin said, adding that the approach was made possible by CRISPR/Cas9 gene editing technology.

The scientists, led by Orkin and Daniel Bauer of Dana-Farber and Boston Children's, and Feng Zhang of the Broad Institute, published their study today in Nature.

The human genome codes for both a fetal version and an adult version of hemoglobin. A mutation in the adult version of the protein causes sickle cell disease. BCL11A became a target of sickle cell disease research after Orkin's laboratory revealed its direct role in the transition from fetal to adult hemoglobin in a 2009 study published in Nature. In 2013, a study led by Orkin and Bauer found the promoter region which controls expression of BCL11A in red blood cells.

"Although fixing the sickle mutation itself would seem the most straightforward approach, it turns out that blood stem cells, the ultimate targets for this kind of therapy, are much more resistant to genetic repair than to genetic disruption," Bauer added. "Therefore, making a single DNA cut that breaks the enhancer solely in blood stem cells could be a much more feasible strategy."

Other experiments performed as part of the study in an animal model revealed that removing the special part of the enhancer affected BCL11A expression only in red blood cells and not in immune or brain cells, where BCL11A is also active.

"These experiments may have revealed the genetic Achilles' heel of sickle cell disease," Orkin said. "Alterations to these specific portions of the enhancer have the same effect as knocking the whole enhancer out altogether, suggesting that this could be a promising strategy to translate into the clinic."

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