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A pair of new gene therapies promise a potentially lasting cure for sickle cell disease by subtly altering the genetic information in patients' bone marrow cells, researchers report.
Sickle cell disease is caused by a genetic defect that causes normally pliable red blood cells to become hard and sticky, forming a c-shape, much like a sickle. These abnormal blood cells die early, causing anemia, and also tend to clot easily in small blood vessels, triggering a wide range of painful and life-threatening complications.
Research going back to the 1980s has shown that sickle cell disease is milder in people whose red blood cells carry a fetal form of hemoglobin, said Hsu, who was not involved in the study. Essentially, the presence of healthy fetal hemoglobin compensates for the mutated hemoglobin that causes red blood cells to stiffen into a sickle shape.
In both new therapies, samples of a person's bone marrow are removed and then genetically edited to switch off BCL11A, a gene that normally suppresses fetal hemoglobin production.
"This is similar to bone marrow transplantation. It's just that you're using your own bone marrow cells, and those stem cells are being corrected. You get your own stem cells back," said Dr. Banu Aygun. She's a pediatric hematology-oncology specialist at Cohen Children's Medical Center in New Hyde Park, N.Y.
The only cure now for sickle cell disease is receiving a bone marrow transplant from a healthy donor, but that's not an option for most patients, said Aygun, who was not involved in the study.
"The best person to match you would be a full sibling, and even when you have a full sibling there's no guarantee that person's typing will match your typing," Aygun said.
The first of the new therapies, developed at Harvard Medical School by a team led by Dr. David Williams, uses a virus to introduce RNA into the extracted bone marrow that turns off BCL11A.
The other study, from German researchers led by Dr. Selim Corbacioglu from the University of Regensburg, relies on CRISPR-Cas9 gene editing to switch off BCL11A.
The CRISPR gene editing method won the 2020 Nobel Prize in Chemistry, and uses chemicals to open up and directly edit DNA sequences, Hsu said.
"It's very, very elegant, almost like a word processor," Hsu said of CRISPR.
Both of the new gene therapy studies were published online Dec. 5 in the New England Journal of Medicine. The German study is also scheduled for presentation on Saturday at the American Society of Hematology's virtual annual meeting.
The findings show that sickle cell disease diminished or went away completely in six patients treated through the Harvard method, and in two patients treated with the CRISPR method.
These new approaches are more subtle than the most advanced experimental gene therapy for sickle cell disease, a treatment developed by U.S. firm Bluebird Bio that already has been administered to dozens of patients, said Dr. Jeffrey Glassberg, director of the Mount Sinai Comprehensive Sickle Cell Program, in New York City.
Bluebird's method "uses a virus to drop an entire gene encoding a new hemoglobin. It's a relatively large genetic payload to deliver, but it works very well," Glassberg said. This process is farthest along the way toward receiving approval from the U.S. Food and Drug Administration.
It's not yet clear whether promoting the production of fetal hemoglobin will work better than directly replacing the defective hemoglobin gene, said Glassberg, who was not involved in the study.
"We already have certain patients who are on medications that raise fetal hemoglobin. They certainly get healthier when we put them on these medicines, but they aren't cured," Glassberg said.
There are many ways that any of these gene therapies can go wrong, Hsu explained. They might fail to produce enough copies of the edited gene to make a difference, the genetic editing might somehow undo itself, or the editing might go awry and, in a worst-case scenario, activate cancer-causing genes located near the actual target.
Because of this, patients will need to be followed at least two years to see whether the therapy lasts, and for as long as 15 years to see if any dangerous side effects emerge, Hsu said.
"When to declare victory is actually not completely clear right now," Hsu said.
Once one or more gene therapies for sickle cell disease have proven out, the next step will be to improve the process to limit the amount of chemotherapy a patient must undergo before the edited cells can be reintroduced into their bodies, Glassberg said.
"For all of these existing therapies, they all have the same issue, that we have to poison you and kill a large amount of the bone marrow that is left in your body," Glassberg said. "Those cells will not go back into your body and set up shop and start making blood if we don't kill most of what's there. That's a very toxic process. Patients get very sick. Their lives are at risk."
Reducing the toxicity of chemotherapy would be a first step, but even better would be a genetic cure that could take place inside the body rather than treating extracted bone marrow cells, Glassberg added.
SOURCES: Lewis Hsu, MD, PhD, chief medical officer, Sickle Cell Disease Association of America; Banu Aygun, MD, pediatric hematology-oncology specialist, Cohen Children's Medical Center, New Hyde Park, N.Y.; Jeffrey Glassberg, MD, director, Mount Sinai Comprehensive Sickle Cell Program, New York City; New England Journal of Medicine, Dec. 5, 2020, online
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