Experimental gene-editing approach holds promise for curing sickle cell disease

The notion of altering a person’s genes to cure disease used to be the stuff of science fiction. But gene editing experiments aimed at the genetic disorder that causes sickle cell disease are now making their way from the laboratory to clinical trials. And researchers supported by the National Heart, Lung, and Blood Institute (NHLBI) are hoping those trials will pave the way for a lasting cure for the deadly disease, which affects millions worldwide.

In sickle cell disease, a single genetic mutation causes the red blood cells to form an abnormal, sickle shape. These sickled cells can clog the blood vessels and deprive cells of oxygen.  This lack of oxygen wreaks havoc on the body, damaging organs, causing severe pain, and ultimately leading to premature death.

If doctors can replace the mutated gene with a normal gene, the disease will be cured, at least in theory. As Matthew Porteus, M.D., Ph.D., has discovered, finding a gene-replacement technique that works is complicated.  He should know: Porteus is a pediatric hematologist and researcher at the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University, and he has spent the past 15 years developing gene editing to treat sickle cell disease.

“The concept of gene editing to treat sickle cell disease is easy to draw on a chalkboard,” he explained recently. “But sometimes what’s easy to draw on a chalkboard is not so easy to implement.”

Porteus, whose research is partly funded by the NHLBI, was speaking to researchers and health professionals attending the NHLBI’s Annual Sickle Cell Disease Clinical Research Meeting in August. He had a lot to report.

In 2016, Porteus led a research team that used a powerful new gene-editing technique, called CRISPR-Cas9, to remove the sickle cell mutation in human blood-forming stem cells in the laboratory.  The researchers then used a harmless virus to add a corrective gene to the blood stem cells. Porteus played a key role in developing a way to use the technique specifically for sickle cell disease.    

In preliminary lab tests of this gene-editing approach, Porteus’ research team collected stem cells from the blood of a small group of volunteers with sickle cell and corrected the sickle-forming mutations in nearly 50 percent of the diseased cells.  They then inserted the gene-edited cells into the bone marrow of laboratory mice specially engineered to accept human cells. 

It worked.  The edited stem cells formed red blood cells, just like normal stem cells do.  Importantly, red blood cells derived from the corrected stem cells produced almost all normal hemoglobin and very little sickle hemoglobin. 

Now Porteus wants to use a similar technique—editing stem cells outside the body and then reinserting them into the bone marrow—to treat actual patients who have sickle cell disease.  If it works, Porteus said, the transplanted bone marrow will produce enough healthy cells to outnumber the sickle cells, essentially curing the patient for life. Porteus hopes to test this approach in late 2018 or early 2019.

Porteus noted that his approach is not the only gene-editing strategy aimed at sickle cell disease.  Other researchers are trying to alter blood stem cells so that they produce an abundance of fetal hemoglobin. It is the main hemoglobin in fetuses and is responsible for transporting oxygen during fetal life and in infants until they are about 6 months old. Fetal hemoglobin protects against complications of sickle cell disease by blocking the effects of sickled hemoglobin. Researchers believe that reactivating fetal hemoglobin production through gene-editing could provide another avenue to a cure. NHLBI is also supporting research on that approach.

“I’m very optimistic that we are going to have a new way of curing sickle cell disease in the future,” Porteus said.  “There may be bumps in the road, but I’m optimistic we will get there.”