Scientists at Fred Hutchinson Cancer Research Center have discovered that editing a small portion of stem cells with CRISPR-Cas9 can provide efficient, long-term reactivation of fetal hemoglobin to treat blood disorders, reported Angus Liu of Fierce Biotech. While currently available gene therapies often deliver a functional gene to replace a defective one, the Hutchinson approach introduces a mutation using the gene-editing system CRISPR-Cas9. They have had promising results from monkey studies designed to boost the production of fetal hemoglobin to treat blood disorders and published the results in the journal Science Translational Medicine.
Mutations in the beta-globin gene create misshapen red blood cells that lead to sickle cell disease and beta-thalassemia. Bluebird Bio’s Zynteglo, which is also called LentiGlobin, adds functional copies of the gene to the patient’s own blood-producing hematopoietic stem cells by means of a lentiviral vector. Instead, the Hutchinson team used CRISPR-Cas9 to reactivate another type of hemoglobin that typically works during fetal development. In studies with monkeys, the approach facilitated long-lasting expression of functional fetal hemoglobin, to offset the defect in adult hemoglobin.
When people have a benign condition called hereditary persistence of fetal hemoglobin (HPHF), they keep expressing gamma-globin. That normally reacts with alpha-globin to form hemoglobin in the womb. Studies have demonstrated that reactivating this fetal hemoglobin has the potential to reverse symptoms in sickle cell disease and beta-thalassemia. Hans-Peter Kiem, senior author of the study, and his colleagues used CRISPR-Cas9 to take away a piece of genetic code to replicate conditions for HPHF, enabling red blood cells to continuously produce elevated levels of fetal hemoglobin.
Kiem’s team’s approach uses hematopoietic stem cells that “engraft,” or settle, in the patient’s bone marrow to create red blood cells with functional hemoglobin. Unlike traditional blood stem cells that have the protein marker CD34, Kiem’s stem cells contain the CD90 antigen. The researchers claim that the CD90 cells can regrow the entire blood and immune system.
The edits were absorbed by 78 percent of target stem cells in the lab dish before they were infused. They were engrafted after transplantation, with edits still showing in 30 percent of blood cells after one year. That resulted in 18 percent of red blood cells expressing fetal hemoglobin, “close to a level sufficient to reverse symptoms of sickle cell disease,” according to Kiem. He believes that they could provide a lifetime cure for the diseases. They could also address the issue of high costs because the method reduces the number of cells required for transplantation by 10-fold. Targeting them requires less editing reagents as well.
“Not only were we able to edit the cells efficiently, we also showed that they engraft efficiently at high levels, and this gives us great hope that we can translate this into an effective therapy for people,” Kiem said.
There could be many other uses in the future. The team found no harmful off-target mutations in edited cells and are running follow-up studies to confirm the safety profile. They hope their technology could help many other patients with blood diseases.
Kiem concluded, “By demonstrating how this select group of cells can be efficiently edited for one type of disease, we hope to use the same approach for conditions such as HIV and some cancers.”