RARE Daily

Study Achieves Proof-of-Concept for Prime Editing to Treat Sickle Cell Disease

April 18, 2023

Rare Daily Staff

Scientists at St. Jude Children’s Research Hospital and the Broad Institute of MIT and Harvard showed that a precise genome editing approach can change mutated hemoglobin genes back to their normal form in sickle cell disease patient cells to restore normal blood parameters, after transplantation into mice.

The findings, published in Nature Biomedical Engineering, showed that a programmable gene editing technology called prime editing can find the disease-causing mutation in the adult hemoglobin gene with high specificity and replace it efficiently with the healthy DNA sequence variant carried by most humans. Prime editing successfully corrected this mutation with up to 41 percent conversion in blood stem cells from SCD patients. Previous research has shown that editing over 20 percent of cells likely translates to therapeutic benefit.

Adding to the approach’s therapeutic promise is the observation that when the researchers transplanted prime-edited cells from four SCD patients into mice, normal hemoglobin production was present in about 45 percent of circulating red blood cells, even up to 17 weeks later. After the transplant, when placed in low-oxygen environments, the red blood cells isolated from the mouse bone marrow reduced sickling by half, from about 67 percent to 37 percent.

Sickle cell disease is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. People with sickle cell disease typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease, and reduced life expectancy.

While the scientists conducted the research in SCD patient cells transplanted into mice, the approach may have advantages over current genome editing methods used in clinical trials, such as Cas9 nucleases, which make double-stranded breaks in DNA that prime editing largely avoids.

The collaborators had previously shown base editing, an alternative genome editing technology, could turn the sickle cell mutation into a benign variant, but not the original healthy sequence, in a 2021 Nature publication. The current study showed prime editing could turn the disease mutation into the original normal gene variant through a T-to-A conversion, which base editing cannot make.

Though the study showed the potential benefits of using prime editing to cure genetic anemias, the researchers cautioned that it also showed limitations. Prime editing requires a time-consuming process to adapt and optimize each step of the protocol, such as designing the prime editing guide RNAs that target the prime editing system to the right DNA region and specify the desired edit.

“These results show efficient prime editing of blood stem cells and that the prime-edited cells maintain their full ability to engraft and repopulate the bone marrow of an animal,” said senior and co-corresponding author David Liu, professor at Broad Institute of MIT and Harvard, whose lab invented prime editing in 2019. “Bringing the ‘search-and-replace’ versatility of prime editing to blood stem cells raises the possibility of applying this technology to treat a wide range of diseases involving blood cells.”

Photo: David Liu, professor at Broad Institute of MIT and Harvard

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