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CRISPR gene editing in humans appears safe, and potentially effective

Crispr Therapeutics and Vertex Pharmaceuticals release first data from sickle cell disease and β-thalassemia clinical trial

by Ryan Cross
November 20, 2019 | APPEARED IN VOLUME 97, ISSUE 46

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Credit: C&EN
A mutation in the β-globin gene causes sickle cell disease and β-thalassemia. Crispr Therapeutics and Vertex Pharmaceuticals are using CRISPR/Cas9 to break the BCL11A gene to boost the production of fetal hemoglobin.

Crispr Therapeutics and Vertex Pharmaceuticals have announced the first preliminary evidence suggesting that CRISPR gene editing can treat genetic diseases in humans. The companies are developing a single experimental CRISPR/Cas9 therapy to treat both sickle cell disease and β-thalassemia.

The partners have only shared data for two patients—one for each disease—so it is too early to draw sweeping conclusions. But in both cases, the gene editing technique appears to be safe and potentially effective.

Sickle cell disease and β-thalassemia are both blood diseases caused by a mutation in the gene for β-globin, a component of hemoglobin. Those mutations prevent hemoglobin from effectively shuttling oxygen throughout the bloodstream.

Crispr Therapeutics and Vertex’s experimental therapy, CTX001, works by turning on production of a protein called γ-globin, which is used in a fetal version of hemoglobin.

In adults, hemoglobin is comprised of two parts α-globin and two parts β-globin. Human fetuses and newborns, in contrast, use two parts α-globin and two parts γ-globin, which yields fetal hemoglobin. Normally, the gene for γ-globin is inactivated after birth, but some people have mutations in a gene called BCL11A that keeps the γ-globin gene turned on.

In the study, clinicians collect patients’ hematopoietic stem cells, which researchers at Crispr Therapeutics then edit with CRISPR/Cas9 to introduce a mutation in BCL11A. Doctors use chemotherapy to wipe out a patient’s bone marrow, making room for the new, edited cells to be infused.

A 19-year-old woman with β-thalassemia who received CTX001 appears stable after 9 months. Nearly all of her circulating red blood cells—99.8% of them—are making fetal hemoglobin, and the majority of hemoglobin in those cells is fetal hemoglobin. A 33-year-old woman with sickle cell disease who received CTX001 4 months ago is making fetal hemoglobin in 94.7% of her circulating red blood cells. So far, fetal hemoglobin makes up just under half of her total hemoglobin, but the percentage has risen over the 4 months of the study.

“I think it looks quite promising,” says Stuart H. Orkin, a blood disease expert at Harvard Medical School, although he cautions that it is still early to draw conclusions. The individuals won’t need to have 100% fetal hemoglobin to be healthy, he adds, but he’d like to see the fraction of fetal hemoglobin rise in the woman with sickle cell disease.

Notably, the companies didn’t report any side effects or unintended consequences of CRISPR gene editing.

Still, the procedure is grueling for the chemotherapy treatment alone, which can kill or damage cells in the body beyond the bone marrow, including germ cells. That’s why Vertex this week also announced a partnership with an Austin, Texas–based biotech company called Molecular Templates to develop new conditioning regimens that specifically targets and kills the bone marrow. Vertex is paying the firm, which normally designs cancer drugs, $38 million up front to develop a class of proteins called engineered toxin bodies, to be administered in advance of CTX001.

Vertex and Crispr Therapeutics aren’t the only companies developing a gene editing approach to treating sickle cell disease and β-thalassemia. Bluebird Bio already has a gene therapy for β-thalassemia approved in Europe, while Editas Medicine and Intellia Therapeutics have preclinical CRISPR/Cas9 programs for both blood diseases. Beam Therapeutics plans on using two new types of CRISPR gene editors—base editors and prime editors—on the diseases. And the Bill & Melinda Gates Foundation and the National Institutes of Health have committed $200 million to developing more affordable therapies that edit hematopoietic stem cells inside the body.

Because sickle cell and β-thalassemia are well understood, it is likely that many scientists and drug companies will continue testing new genetic technologies on the diseases. “It’s not the end of the road,” Orkin says. “There are lots of different strategies. We’ll have to wait and see who wins out.”

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