Changes to a small stretch of dna called an enhancer may circumvent the genetic defect behind sickle-cell disease, say HMS researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.
This finding, reported online in Nature on September 16, creates a path for developing gene-editing approaches for treating sickle cell and other hemoglobin disorders, such as thalassemia.
The enhancer identified by the researchers controls the molecular switch BCL11A. This switch determines whether a red blood cell produces the adult form of hemoglobin, which is mutated in sickle-cell disease, or a fetal form that counteracts, and is unaffected by, the effects of the sickle mutation. Other studies have found that sickle-cell patients with elevated levels of fetal hemoglobin have a milder form of the disease.
The new study, led by Stuart Orkin ’71, the HMS David G. Nathan Professor of Pediatrics at Dana-Farber/Boston Children’s; Daniel Bauer, an HMS assistant professor of pediatrics at Boston Children’s Hospital; and Feng Zhang of the Broad Institute of Harvard and MIT, was spurred by the discovery that naturally occurring beneficial variations in the DNA sequence in this enhancer decrease BCL11A activity only in red blood cells.
Using recently developed CRISPR-based gene-editing tools, the researchers systematically cut out tiny sections of DNA throughout the enhancer in blood stem cells from human donors. They then allowed the cells to mature into red blood cells and found that the amount of fetal hemoglobin the cells produced had increased substantially.
The team’s experiments revealed a specific location in the enhancer that, when eliminated, leads to production of high levels of fetal hemoglobin. Additional work showed that these effects occur only in red blood cells.
“We’ve now targeted the modifier of the modifier of a disease-causing gene,” says Orkin. “It’s a very different approach to treating disease.”
The data provide proof of principle that targeted edits to BCL11A’s enhancer in human blood stem cells could be an attractive approach for curing sickle-cell disease and related conditions.
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