The U.S. National Institutes of Health (NIH) has awarded researchers at Rice University a four-year, $2.45-million grant to support the development of a CRISPR/Cas9-based gene editing treatment for sickle cell disease (SCD).
Funding preclinical research, the R01 grant seeks to advance a way to modify the stem cells responsible for producing damaged blood cells in SCD patients.
SCD is caused by a single mutation in the HBB gene, which codes for the beta subunit of hemoglobin, a protein found in red blood cells that transports oxygen throughout the bloodstream. This mutation results in distorted and fragile red blood cells.
The goal of the newly funded research is to directly substitute the mutated hemoglobin gene in HSPCs with a normal version, which would then produce healthy red blood cells. This is done by collecting a patient’s HSPCs, replacing the faulty gene by using the CRISPR/Cas9 technique, and reintroducing the edited cells back into the patient.
Building on a previous study conducted in mice, the team at Rice found that, on average, 25% of HSPCs from patients properly integrated the replacement DNA and showed normal hemoglobin production.
However, the researchers documented unwanted effects that need to be addressed before tests can be done in humans.
One of the issues was the efficiency of the CRISPR/Cas9 editing. Some of the HSPCs that showed signs of CRISPR/Cas9 activity did not have repaired DNA, and others showed no editing activity at all.
“There’s no integration of donor DNA in around 45% of cells that show cutting, and there’s always a fraction that has no cutting,” said Gang Bao, PhD, the lead researcher, in a press release.
Also, the researchers found that some HSPCs with cutting but no new DNA produced fetal hemoglobin, a version of hemoglobin found only from about seven months before birth to about six months after. While fetal hemoglobin may be beneficial to people with SCD, the researchers do not understand how their gene editing technique caused its production.
Another complication that could arise in the editing of HSPCs is chromosomal rearrangements, or errors in the way that the healthy gene is introduced into these cells’ genome.
The investigators also want to make sure that CRISPR-Cas9 would not result in beta thalassemia, a disorder that results in reduced hemoglobin production. Beta thalassemia is caused by mutations to the same hemoglobin gene mutated in SCD patients.
“Before we address these three issues due to Cas9 cutting, i.e., mechanism of inducing fetal hemoglobin, chromosomal rearrangements and the possibility of causing beta thalassemia, applying for a clinical trial might be premature,” Bao said.
In its NIH-funded project, the team intends to use sophisticated DNA sequencing techniques to measure the number of chromosomal rearrangements and the risk of beta thalassemia.
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