and a sickled one
Image by Betty Pace
CRISPR-Cas9-mediated genome editing might be a feasible approach for treating sickle cell disease (SCD), according to a group of researchers.
The team used CRISPR to edit hematopoietic stem and progenitor cells (HSPCs) from patients with SCD, which resulted in the production of red blood cells (RBCs) that had enough fetal hemoglobin to be healthy.
The researchers believe this approach might prove effective in treating beta-thalassemia as well.
“Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin,” said study author Mitchell J. Weiss, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“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 . . . . We have found a way to use CRISPR gene editing to produce similar benefits.”
Dr Weiss and his colleagues described this method in Nature Medicine.
The researchers noted that SCD and beta-thalassemia become symptomatic when fetal gamma-globin expression from 2 genes, HBG1 and HBG2, decreases and the expression of adult beta-globin increases, which shifts RBC hemoglobin from the fetal form to the adult form.
Reversing this shift can raise levels of fetal hemoglobin and ameliorate the symptoms of beta-thalassemia or SCD.
The team also pointed out that, in people with a benign genetic condition known as hereditary persistence of fetal hemoglobin (HPFH), mutations attenuate gamma-globin-to-beta-globin switching, which causes high levels of fetal hemoglobin expression throughout the patients’ lives.
So the researchers set out to mimic this phenomenon in HSPCs from patients with SCD.
The team performed CRISPR–Cas9-mediated genome editing of the HSPCs to mutate a 13-nt sequence present in the promoters of the HBG1 and HBG2 genes.
In this way, they were able to recapitulate a naturally occurring HPFH-associated mutation, so the HSPCs produced RBCs with increased fetal hemoglobin levels.
“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,” Dr Weiss said.
“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.”
Recently, scientists have used several genome-editing approaches to manipulate HSPCs for the possible treatment of SCD and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching.
“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,” Dr Weiss said.
He and his colleagues noted that, at this stage, it is still too early to begin clinical trials of their approach. The researchers want to refine the genome-editing process and perform other experiments to minimize potentially harmful off-target mutations before clinical trials are considered.
In addition, they said it will be important to compare the different genome-editing approaches head-to-head to determine which is safest and most effective.
