The researchers, led by Hans-Peter Kiem, used CRISPR to modify hematopoietic stem cells from nonhuman primates. They then introduced a naturally occurring mutation that increases the amount of fetal hemoglobin.
Researchers with the Fred Hutchinson Cancer Research Center utilized CRISPR/Cas9 gene editing to modify a subset of blood stem cells to reverse the clinical symptoms of sickle cell disease and beta-thalassemia. It’s the first time anyone has specifically edited the genome of this subset of adult blood stem cells that create all the cells in the blood and immune system. They published their research in the journal Science Translational Medicine.
The researchers, led by Hans-Peter Kiem, used CRISPR to modify hematopoietic stem cells from nonhuman primates. They then introduced a naturally occurring mutation that increases the amount of fetal hemoglobin.
“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,” stated senior author Kiem, director of the Stem Cell and Gene Therapy Program and a member of the Clinical Research Division at Fred Hutch. “Targeting this portion of stem cells could potentially help millions of people with blood diseases.”
The researchers chose a gene related to sickle cell disease and beta-thalassemia. Both are caused by a mutation in how hemoglobin is manufactured. Other studies indicated that symptoms can be reversed by reactivating a version of hemoglobin that occurs during fetal development but is switched off by the time we are about one year old.
They used CRISPR to remove the part of the gene that turns off fetal hemoglobin protein production. This resulted in red blood cells being able to continuously produce increased levels of fetal hemoglobin.
In their study, 78% of targeted cells took up the edits in Petri dishes prior to infusion. Once infused, the edited cells embedded, multiplied and started churning out blood cells, 30% of which contained the edits. This caused up to 20% of red blood cells to have fetal hemoglobin, which is known to reverse disease symptoms in sickle cell disease and thalassemia.
“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 stated. “Twenty percent of red blood cells with fetal hemoglobin—what we saw with this method—would be close to a level sufficient to reverse symptoms of sickle cell disease.”
They hypothesize that performing these genetic manipulations on a smaller pool of cells would decrease safety concerns and reduce the possibility of off-target effects, a significant worry with CRISPR editing. The next step is additional studies to make sure there are no long-term effects.
“Since the CRISPR technology is still in early stages of development, it was important to demonstrate that our approach is safe,” stated Olivier Humbert, a staff scientist in the Kiem Lab. “We found no harmful off-target mutations in edited cells and we are currently conducting long-term follow-up studies to verify the absence of any undesired effect.”
If the approach is deemed safe, it could lead to human clinical trials. This particular subset of stem cells is a significant candidate to deliver gene therapy because they represent only 5% of all blood stem cells, the processes would require fewer supplies and possibly be less expensive.
