Inherited mutations, specifically a defect in the adult globin gene, are responsible for the disorder. The mutated gene affects the production of hemoglobin, a protein in red blood cells that transports oxygen throughout our body.
“What’s interesting is that when babies are born, they don’t show symptoms at first, even if they have the mutation, because, at that stage, they’re still expressing fetal globin and not globin yet. It’s because we have different hemoglobin genes that we express at different stages of development,” Quinlan said.
Quinlan adds: “When fetal globin is turned off and adult globin is turned on, which happens around the first year of life, symptoms begin to manifest.
When that happens, the red blood cells take on an irregular, sickle-shaped shape and block small blood vessels, causing pain, organ damage, and early death.
“The goal of our study was to find out how we could reverse the fetal-to-adult globin transition, so that the patient continues to express fetal globin throughout life, rather than the globin genes. Maturity mutations cause blood cells to harden and block blood vessels. Quinlan said.
For the study, the team collected data on rare families of fetal globin expression throughout life.
They then used CRISPR gene editing to replicate some of these large patient deletions and the small bit of deletion they all have in common, in laboratory cell lines.
“CRISPR allows us to ‘cut’ bits of DNA out of cells grown in the lab, to modify the gene and see what the result is – it’s essentially a tool to find out,” Quinlan said. Genes operate inside living cells.
“We found that even a slight deletion was enough to cause fetal globin to increase and adult globin to decrease, which suggests that we have identified a key mechanism that could explain why high levels of Fetal globin remains elevated in these asymptomatic patients.”
Quinlan mentioned that “effectively, by removing globin ‘on the switch’ of the adult, we made the globin ‘on the switch’ of the fetus ‘active'”.