Base Editing Could Correct Mutation Underlying Sickle Cell Disease

A team led by researchers at the Broad Institute of MIT and Harvard and St. Jude Children's Research Hospital has now demonstrated a base editing approach that efficiently corrects the mutation underlying Sickle cell disease (SCD) in patient blood stem cells and in mice. Their study was published in Nature.

The team first introduced the adenine base editor into isolated blood stem cells from human SCD patients. In these experiments, up to 80 percent of the pathogenic hemoglobin variants were successfully edited into the benign Makassar variant, with minimal instances of the editor causing undesired changes to hemoglobin. The researchers transferred these edited blood stem cells into a mouse model to observe how they functioned in live animals. After 16 weeks, the edited cells still produced healthy blood cells.

"Sixteen weeks after transplantation, the total frequency of the edit maintained in stem cells—which could contain edits in both copies of their hemoglobin gene, in only one copy, or in neither copy—was 68 percent. And we were particularly excited to see that nearly 90 percent of cells contained at least one edited copy of hemoglobin," explains researcher Gregory Newby. "Even those cells with just one edited copy appeared to be protected from sickling."

In a separate set of experiments, the researchers took blood stem cells from mice harboring the human sickle cell disease variant, edited them, and transplanted the edited cells into another set of recipient mice. Control mice transplanted with unedited cells showed typical symptoms: sickled red blood cells, consequences of short red blood cell lifetime, and an enlarged spleen. In contrast, mice transplanted with edited cells were improved compared to controls by every tested disease metric, with all measured blood parameters observed at levels nearly indistinguishable from healthy animals. 

Finally, to confirm durable editing of the target blood stem cells, the researchers performed a secondary transplant, taking bone marrow from mice that had received edited cells 16 weeks previously and transferring the blood stem cells into a new set of mice. In the new animal cohort, edited cells continued to perform similarly to healthy blood stem cells, confirming that the effects of base editing were long-lasting. The team determined that editing at least 20 percent of pathogenic hemoglobin genes was sufficient to maintain blood metrics in the mice at healthy levels.