Gene Therapy for Sickle Cell Takes Another Step Forward

 A new gene therapy shows early promise against sickle cell anemia, researchers say.

The therapy targets the genetic flaw that causes sickle cell. In a small group of patients, researchers said the therapy appears safe and effective enough to keep moving forward into larger trials.

"We've been talking about using gene therapy for sickle cell anemia for years. Now it's finally coming of age," said Dr. John Tisdale, a scientist with the U.S. National Institutes of Health who is leading the ongoing research.

Sickle cell anemia is an inherited disease that mainly affects people of African, South American or Mediterranean descent. In the United States, about 1 in 365 black children is born with the condition, according to the NIH.

It arises when a person inherits two copies of an abnormal hemoglobin gene -- one from each parent. Hemoglobin is an oxygen-carrying protein within red blood cells.

When those cells contain "sickle" hemoglobin, they become crescent-shaped, rather than disk-shaped. They tend to be sticky and can clot -- causing symptoms such as fatigue and shortness of breath.

Many people with sickle cell also suffer bouts of severe pain due to poor blood circulation. Over time, the disease can damage organs throughout the body, leading to complications like kidney disease and stroke.

"It's a devastating disease," Tisdale said. "People often die early, in their 40s."

He presented the preliminary results this week at the American Society of Hematology's annual meeting, in San Diego.

There are treatments, such as the cancer drug hydroxyurea, which can help prevent severe pain and certain other complications. But the medications don't change the course of the disease.

There is one way to "fix" it, Tisdale said: a bone marrow transplant.

The procedure destroys a person's existing bone marrow stem cells -- which are producing the faulty red blood cells -- and replaces them with stem cells from a healthy donor.

The problem, Tisdale said, is that the donor has to be a genetic match (usually a sibling) who is free of sickle cell.

"That covers about 10 percent of patients," he said. "We need something for the other 90 percent."

That's where gene therapy could come in. Tisdale explained the basics: First, doctors remove a supply of blood-forming stem cells from the patient, before using chemotherapy to wipe out the remaining stem cells.

Next, they use a modified virus to deliver a "therapeutic" gene into the extracted stem cells. The gene is an "anti-sickling" version of the beta globulin gene, which is mutated in sickle cell.

Those genetically modified stem cells are then infused back into the patient -- with the aim of repopulating the body with normal red blood cells.

Tisdale's team initially treated seven patients with severe sickle cell who'd suffered complications from the disease. The gene therapy did produce new red blood cells, but at fairly low levels. So the researchers tweaked the procedure, and tested it in six other patients.

Of those patients, four had been followed for about three months on average as of May 2018. By that point, all had at least as many normal red blood cells as sickle-affected cells.

"We're also seeing a resolution of anemia and pain," Tisdale said.

The short-term side effects included fever caused by a drop in white blood cells, inflammation in the mouth, and chest pain.

This is not the first report of gene therapy being used for sickle cell. Last year, French researchers described the case of a teenage boy who was doing well 15 months after receiving gene therapy. Tisdale said that approach was very similar to the one his team used.

So far, research has focused on people with severe sickle cell.

But ultimately, the hope is to use gene therapy earlier in the course of the disease to prevent complications, said Dr. Caterina Minniti, director of the Montefiore Medical Center's Sickle Cell Center for Adults in New York City.

Minniti, who was not involved in the research, called the early results "very exciting."

Still, she cautioned that it will be a while before the approach is available for widespread use. With any gene therapy, Minniti noted, there are always questions about the long-term "stability" of the inserted gene, and whether it could have any unintended effects in the body.

But overall, she said, the outlook for sickle cell patients is improving. A new drug for preventing complications, called Endari (L-glutamine), received U.S. approval last year, and others are on the way.

"The development of therapies has dramatically accelerated in recent years," Minniti said.

Research presented at meetings is usually considered preliminary until published in a peer-reviewed medical journal.

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