cientists have taken an important step toward using CRISPR-Cas9 genome-editing to cure sickle cell disease, repairing the disease-causing mutation in blood-forming cells taken from patients. Some edited cells, injected into lab mice, both survived in the animals’ bone marrow and turned into red blood cells — a hint that CRISPR’d cells would  would produce healthy hemoglobin in people. This is the first such experiment to get levels of healthy hemoglobin that might be high enough to cure patients.

Why it matters:

Sickle cell is a painful and sometimes fatal disease that affects about 100,000 people in the US. Many scientists consider it an embarrassment that, although the mutation responsible for sickle cell was discovered in 1949, the revolution in molecular biology and genetics has hardly touched it.

That is finally changing. Researchers at Dana-Farber/Boston Children’s Hospital and elsewhere have reported enough progress in cell and animal experiments with virus-based gene editing to plan a human study of at least one genome-editing strategy in a few months. The new study, published on Wednesday in Science Translational Medicine, takes a different approach, increasing the chance that something will eventually be able to engineer blood cells so they produce healthy hemoglobin rather than the mutated, sickled kind.


You’ll want to know:

The experiment was classic CRISPR, the genome-editing technology that has raised hopes of curing myriads of genetic diseases. Scientists at the University of California, Berkeley’s Innovative Genomics Initiative built molecules called guide RNA, which home to the beta-globin mutation; they connected the guides to an enzyme (Cas9) that snips out the mutation and to DNA that serves as a repair template to correct the mutation. (Guide + enzyme + optional repair template = CRISPR.) They drew blood from sickle-cell patients, isolated precursor cells that mature into red blood cells, mixed those with the CRISPR constructs, and gave the cells an electric shock that made them open their pores to CRISPR like the Trojans opened their gates to the Greeks’ horse. 

CRISPR did as it was programmed to. In about one-quarter of cells, the guide RNA made a beeline for the mutation, Cas9 snipped out the mutation, and the cell used the repair template to insert a healthy version. In the other cells, the editing didn’t take, which is typical for CRISPR. (The researchers created a video explaining their experiment.)

When the CRISPR’d cells were transplanted into the bone marrow of seven mice, 2 percent to 6 percent of the cells retained the CRISPR’d hemoglobin for all 16 weeks of the study. (The range reflects the fact that, among other things, some patients’ cells were easier to CRISPR than others’, for unknown reasons.) A few percent might seem low, said Jacob Corn, scientific director of the Innovative Genomics Initiative and a co-leader of the study, but studies suggest that having just 2 percent to 5 percent of healthy red blood cells could be enough to cure sickle cell.

In healthy people, blood cells are round and flexible. But in people with sickle cell disease, blood cells are deformed and cause a range of health problems. Hyacinth Empinado/STAT

In other approaches to edit the sickle-cell mutation, “the rate of editing was much less than 1 percent,” said Dana Carroll of the University of Utah, a genome-engineering veteran who helped lead the study. “We thought that with [CRISPR] we could get much higher efficiency, but it really was a shot in the dark.”

But keep in mind:

As always, what worked in mice might not in patients. A constant concern with CRISPR is that it edits genes it isn’t supposed to, because the guide RNA mistakes a healthy region of DNA for the mutation. Testing the most likely of these “off-target” sites, the scientists found that the one that was mistakenly CRISPR’d the most often wasn’t a gene at all, or even near any genes. Other off-target sites were CRISPR’d in fewer than 0.10 percent of cells. But even that low level of error might be dangerous, perhaps triggering a cancer-causing gene, so Corn and his team are running more animal studies of whether their CRISPR approach will be safe.

What they’re saying:

Dr. Vijay Sankaran, a hematologist at Boston Children’s Hospital who did pioneering work on the genetics of sickle cell, called the new study “quite exciting.” But the 2-to-6 percent success rate might not be enough to help patients, he warned. And some of the inadvertent DNA changes could cause other serious diseases: “A patient with sickle cell disease being treated using this approach may end up having beta thalassemia instead,” he said.

The bottom line:

Corn said his group is aiming to launch a clinical trial using this approach within five years. They still have to prove in more lab animals that CRISPR’ing blood-forming cells is safe, let alone effective for sickle cell. But the very fact that scientists are finally attacking sickle cell with 21st-century genetics improves the odds that something will work in this long-neglected disease.

This story has been corrected to clarify what kind of edited cells were implanted in mice.

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