Gene editing of human blood-forming stem cells can fight sickle cell disease

A team of scientists has developed a new way to use CRISPR gene editing to treat sickle cell disease and beta-thalassemia in blood cells isolated from patients.

"Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin," said Mitchell J. Weiss, MD, PhD, chair of the St. Jude Department of Hematology. "It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia, genetic forms of severe anemia that are common in many regions of the world. We have found a way to use CRISPR gene editing to produce similar benefits."

Sickle cell disease and beta-thalassemia damage the hemoglobin within the body, diminishing the amount of oxygen being carried throughout the body. Fetal and adult hemoglobin are two different means red blood cells can carry oxygen. Sickle cell disease and beta-thalassemia are caused by a gene mutation.

After the birth, the amount of adult hemoglobin overpowers the fetal hemoglobin, which contains “gamma” subunits. Adult hemoglobin then becomes dominant over the fetal mutation.

Experts have known for some time that inhibiting or reversing "gamma-to-beta" switching of hemoglobin subunits can raise levels of fetal hemoglobin in adults and significantly ameliorate the debilitating symptoms of beta-thalassemia or sickle cell disease.

"Our work has identified a potential DNA target for genome editing–mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia," said Weiss. "We have been able to snip that DNA target using CRISPR, remove a short segment in a "control section" of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells." When the scientists edited the DNA of blood-forming stem cells derived from patients with sickle cell disease, they were able to activate those genes and produce red blood cells that had enough fetal hemoglobin to be healthy.

Even though clinical trials have not yet been tested, scientists are set on defining gene editing as the major treatment in these diseases.

“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system," said Weiss.