Current Sickle Cell Disease Treatment and What's Coming

Adults afflicted with sickle cell disease have difficulty leading normal lives. New, effective treatments for debilitating symptoms cannot arrive soon enough, but help may be on the horizon.

While rare, sickle cell disease (SCD) is the most common hemoglobinopathy among people in the United States. It's an autosomal recessive disorder that causes blood cell dysfunction, and it's a global health problem.

Part one of this series explained the scope of SCD, who is most affected by it and its effects on the body, including pain, tissue and organ damage, and strokes. We also introduced Marlo McGee, a longtime SCD patient who was misdiagnosed for years.

Part two takes a close look at sickle cell disease treatment. What is the current gold standard? What's in the works and can gene therapy be a solution for patients such as McGee?

The standard approved treatment for SCD is hydroxyurea, an oral medication, according to Stuart Orkin, M.D., the David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School and a Howard Hughes Medical Institute investigator.

"What hydroxyurea does in many, many patients is it reduces their pain, certainly, and it changes the properties of the red cell a little," Orkin said. "The red cells get a little larger, and so the hemoglobin gets a little more diluted."

With its "constellation of effects," as Orkin put it, hydroxyurea results in diminished SCD crises for a number of patients, especially children.

"Now, some patients don't respond at all, so it's by no means a panacea," he said. "But what it has tended to do is reduce the problems in kids and sort of move that to the adults."

In a review article published in 2018 in the journal Pediatric Clinics of North America, Emily Meier, M.D., of Indiana University Health, wrote that hydroxyurea increases the life span of erythrocytes (red blood cells), decreases the rate at which those cells rupture, tends to be well tolerated by patients and exhibits minimal irreversible side effects. The drug directly affects and can suppress bone marrow (myelosuppression), so patients do require close monitoring at the initiation of treatment and when the dosage is changed, the author added.

Unfortunately, the drug didn't work for McGee, whose father, Ernie, explained it had no effect. At one point, while she was incarcerated in Riverside County in California, she started receiving blood transfusions every three weeks after finally seeing a sickle cell specialist. The transfusions enabled her to live more or less pain-free, and she earned an associate's degree while in jail as a result, her father said. Then the specialist left and McGee's condition deteriorated, leaving her with painful episodes again.

According to Meier's review, blood transfusion therapy has a limited number of applications for sickle cell disease. Simple erythrocyte transfusions, wherein the patient's own blood is not removed, can be used to help SCD sufferers experiencing acute or severe anemia, acute chest syndrome and other disease-related conditions.

Partial or full-exchange transfusions can benefit SCD patients with severe acute chest syndrome and acute or impending cerebrovascular events, when the brain and the blood vessels supplying it are or will be impacted. Depending on the circumstances, either type of transfusion might be used in SCD-induced conditions such as hepatic sequestration, when an abnormal amount of red blood cells accumulate in the liver, and multisystem organ failure. Severe SCD crises can potentially affect all organ systems.

Other treatment options include the amino acid l-glutamine, which the Food and Drug Administration approved in 2017 to reduce acute complications of SCD.

However, neither FDA-approved SCD drug, hydroxyurea or l-glutamine, can completely prevent the progression of the chronic disease.

Gene therapies have been of interest in SCD treatment for some time due to the genetic mutation that causes the disorder.

"Gene therapy is under intense investigation and holds promise for curative therapy," said Cage Johnson, M.D., a professor emeritus of medicine in the hematology division at the University of Southern California Keck School of Medicine in Los Angeles and a past director of the Sickle Cell Center there.

Orkin said one gene therapy approach involves the use of a virus to bring a normal hemoglobin gene into stem cells.

"And that, so far, has been moderately successful," he said. "Part of the problem has to do with how well this virus will express the new hemoglobin you give it."

Orkin said this approach is being spearheaded by a company in Boston called bluebird bio. The company has experimental trials that could go up for FDA review yet in 2022. Orkin said the trials are critical because they were on hold and then restarted because the SCD patients participating in the study had complications—not due to the therapy, but probably the bad luck of the disease.

Orkin said gene editing—a kind of gene therapy that uses a patient's own cells, thereby avoiding immune rejection—entails modification of the blood stem cell genes to either correct or compensate for genes. He called it quite effective based on results from trials conducted thus far.

Gene editing for SCD patients often involves increasing fetal hemoglobin, he said.

"We know fetal hemoglobin is a good replacement for sickle hemoglobin and we know it's a good inhibitor of the signaling process, and we know about how much fetal hemoglobin you need in a cell to get over the 'threshold,' it's called, which would be enough to make a patient essentially well," Orkin said.

He added that CRISPR Therapeutics and Vertex Pharmaceuticals are now collaborating on gene editing therapy, which has been used to treat a substantial number of people with sickle cell disease.

"And those patients, at least by report, once they've had the gene editing, do increase their fetal hemoglobin," Orkin said. "The patients have no more crises and they're essentially well. Now, their blood may not be entirely normal in terms of turnover and stuff like that, but from a clinical standpoint, they're essentially well."

Another gene therapy of sorts inhibits the repressor of fetal hemoglobin so as to increase it, Orkin added. About half a dozen patients treated with this approach have achieved results similar to those produced by gene editing. Some of their complications are even reversible over time, he said.

"Second-generation gene editing" treatments are also in the works, Orkin said. Most of them focus on changing the sickle mutation back to normal or something benign, or on raising fetal hemoglobin without CRISPR, a tool for editing genomes.

Gene therapies aren't likely to solve the global public health problem of sickle cell disease, given its scale and the limited resources available, Orkin acknowledged, though advances in treatment involving the "injection of gene-editing machinery" as part of a lipid nanoparticle, like with the COVID-19 vaccine, could change the equation.

"You can put RNA in a particle, inject it like a vaccine, and if you could then get it to go to the right place and edit—the bone marrow stem cells, in vivo gene therapy—that would revolutionize things," he said. "The issue is whether or not the current technology is efficient enough to accomplish that. My own reading, my own impression at this stage, is we're not there."

For adults who endure ongoing episodes associated with chronic SCD, new types of sickle cell disease treatment cannot become available soon enough, as McGee's experience attests.

"The days of not getting prompt treatment have harmed her body, and you can't go back and repair it," said McGee's father, Ernie. "So, internally, I know she's messed up…just trying to survive."

Orkin remains cautiously optimistic and said we're in an interesting time in which the latest methods are being applied to a disease we've known about since the early 1900s.

"I think, for the first time, we can actually very soon say to patients, 'We can make you better [and] maybe cure you,' and feel that it will be a safe therapy," he said, while acknowledging that patients in minority populations in the United States might be gun-shy about undergoing a new therapy, given the history of the Tuskegee Study and other unethical, unsafe and/or exploitative medical interventions.

"But I think the results are going to be so clear-cut that we can, I think, soon say with confidence, we can make their lives better," Orkin said. "And I think it's a real turning point."