The Revolutionary Treatment of Sickle-Cell Disease With CRISPR

Friday - December 8 2023, 08:31 UTC - 11 months ago

The world's first commercial gene-editing treatment, Casgevy, is set to revolutionize the lives of those with sickle-cell disease. This therapy involves a molecular bank shot – editing BCL11A, a gene that turbo-boosts the inhibitor and prevents the production of fetal hemoglobin in adult bodies. This will cause more fetal hemoglobin to be produced. Through early trials, there is proof that this gene-editing therapy is revolutionizing and potentially curing patients with sickle-cell disease.

The world’s first commercial gene-editing treatment is set to start changing the lives of people with sickle-cell disease. It’s called Casgevy, and it was approved last month in the UK. US approval is pending this week.The treatment, which will be sold in the US by Vertex Pharmaceuticals, employs CRISPR, the Nobel-winning molecular scissors that have had journalists scrambling for metaphors: "Swiss Army knife," "molecular scalpel," or DNA copy-and-paste .

Indeed, CRISPR is revolutionary because scientists can so easily program it to cut DNA at precise locations they choose.But where do you aim CRISPR? That’s the lesser-known story of the sickle-cell breakthrough. The disease is caused by faulty hemoglobin, the molecule that carries oxygen in the blood. To cure it, though, Vertex and its partner company, CRISPR Therapeutics, aren’t fixing the genes responsible for the mutation that leaves those molecules misshapen .

Instead, the new treatment involves a kind of molecular bank shot—an edit that turns on fetal hemoglobin, a second form of the molecule that we have in the womb but lose as adults.You can think of how the edit works as a kind of double negative. It adds a misspelling to the turbo-booster of another gene, BCL11A, that is itself what inhibits the production of fetal hemoglobin in adult bodies. Without that booster, there’s less inhibition, and more fetal hemoglobin .

Got it?"When you inhibit the enhancer, you inhibit the inhibitor," says Daniel Bauer, a professor at Boston Children’s Hospital and Harvard University, who helped work it out. "It is kind of complicated."The important thing is a happy ending—and this edit really works. Some patients say they lived in fear of dying, either from an acute attack of sickling (when their red blood cells start blocking vessels) or from slow, insidious organ damage .

Now early volunteers say they’re grateful—and, after living with disease their whole lives, even a little shocked—to be cured.Newborn theoryThe idea that fetal hemoglobin can protect against the disease is an old one. Sickle-cell is most common in people with African ancestry. A doctor on Long Island, Janet Watson, had noticed in 1948 that newborns never showed its signs—the main one being misshapen, crescent-shaped red blood cells .

That was pretty odd for an inborn condition."Sickle-cell disease should occur in infancy as often as later in life," Watson wrote. But since it didn’t, Watson hypothesized that the fetal form of the molecule, active in the womb, was protecting babies for a few months after birth, until it was replaced by the adult version: "The theory that at once presents itself is that fetal hemoglobin is unable to produce sickling .

"She was right. But it took another six decades to learn how the switch-over worked—and how to flip it back. Many of those discoveries were made in the laboratory of Stuart Orkin, a Harvard researcher who published his first paper in 1967 and who’s lived through several eras of research on blood diseases, starting near the dawn of molecular biology."I am one of the last men standing," Orkin told me with a grin when I met him for a corned-beef sauerkraut lunch in Boston recently .

The world's first commercial gene-editing treatment, Casgevy, is set to revolutionize the lives of those with sickle-cell disease. In order to cure it, Vertex and CRISPR Therapeutics are using CRISPR, a Nobel-winning molecular scissors that is programmed to cut DNA at precise locations. Vertex and this partner company are not fixing the genes responsible for mutations, instead they are using a kind of molecular bank shot – editing BCL11A, a gene that turbo-boosts the inhibitor and prevents the production of fetal hemoglobin in adult bodies .

This will cause more fetal hemoglobin to be produced. The idea that fetal hemoglobin can protect against the disease is an old one, first being proposed by doctor Janet Watson in 1948. Since then, the knowledge and understanding of how this switch-over works come from the laboratory of Stuart Orkin, a Harvard researcher. Through early trials, there is proof that this gene-editing therapy is revolutionizing and potentially curing patients with sickle-cell disease .