Gene editing study reveals possible 'Achilles heel' of sickle cell disease

Researchers from Dana-Farber/Boston Children's Cancer and Blood Disorders Center have found that changes to a small stretch of DNA may circumvent the genetic defect behind sickle cell disease (SCD). The discovery, published in the journal Nature, creates a path for developing gene editing approaches for treating SCD and other hemoglobin disorders, such as thalassemia.

This stretch of DNA, called an enhancer, controls the molecular switch BCL11A. This switch, in turn, determines whether a red blood cell produces the adult form of hemoglobin — which in SCD is mutated — or a fetal form that is unaffected by and counteracts the effects of the sickle mutation. Other studies indicate that sickle cell patients with elevated levels of fetal hemoglobin have a milder form of the disease.

The new Nature study — led by Stuart Orkin, MD, and Daniel Bauer, MD, PhD, of Dana-Farber/Boston Children's, and Feng Zhang, PhD, of the Broad Institute of MIT and Harvard — was spurred by the discovery that naturally occurring beneficial variations in the DNA sequence in this enhancer dial down BCL11A only in red blood cells.

To mimic and improve upon the effects of these variations, the research team used recently developed CRISPR-based gene editing tools to systematically cut out tiny sections of DNA step-by-step along the entire length of 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 cut leads to production of high levels of fetal hemoglobin. Parallel experiments in an animal model revealed that removal of this part of the enhancer affected BCL11A's expression only in red blood cells, not in immune or brain cells, where BCL11A is also active. These findings show that the effects are restricted to red blood cells, and that other cell types are unaffected.