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Two teams target BCL11A in different ways to treat sickle cell disease

The New England Journal of Medicine
Reuters Health - 07/12/2020 - Separate teams of doctors using related gene-therapy techniques are reporting positive results in their early-stage efforts to cure severe sickle cell disease, the genetic defect that turns red blood cells misshapen and brittle.

Both techniques turn down the activity of a gene known as BCL11A, which suppresses production of the type of hemoglobin that fetuses make. The result: fetal hemoglobin, which doesn't carry the defect that makes adult red blood cells sickle, makes a comeback, reducing or eliminating symptoms.

One technique uses a manipulated virus and microRNA to suppress BCL11A. The other employs CRISPR-Cas9 gene editing technology to switch off the gene. Both require patients to receive a bone-marrow transplant of their own manipulated cells.

All six patients whose blood was treated with the deactivated virus remain healthy with reduced symptoms or no symptoms after seven to 29 months. One 33-year-old woman with sickle cell disease was treated with CRISPR and is doing well after 21.5 months.

In a second CRISPR volunteer, a 19-year-old woman who has been followed for 18 months, the technique was used to cure beta thalassemia, where BCL11A also plays a role.

Side effects were attributable to those seen when the bone marrow is replaced.

Details of both tests are reported in the New England Journal of Medicine. The CRISPR results were also released at the annual meeting of the American Society of Hematology.

Sickle cell disease affects about 100,000 people in the United States.

"We're very encouraged by the proof of principle that targeting BCL11A is clearly showing a strong induction of fetal hemoglobin. And we know from decades of all kinds of research that high fetal hemoglobin levels are very effective in decreasing the problems in sickle cell disease. It's very encouraging that we have seen a clinical benefit so far," lead author Dr. Erica Esrick of the Dana-Farber/Boston Children's Cancer and Blood Disorders Center told Reuters Health by phone. She and her team used the genetically engineered virus.

"This was a safety study and the results of this have allowed us to plan a much bigger national, multi-center study to really show the effect on the disease itself," senior author Dr. David Williams, also of Dana-Farber and Boston Children's Hospital, said in the same interview. "It will get started early in 2021."

"This has never been done before in humans. It seems to be safe and the effects we're seeing are encouraging enough for us to want to do more patients in the next study," he said.

Among the six volunteers treated at Boston Children's Hospital, fetal hemoglobin came to make up 20.4% to 41.5% of the hemoglobin in the blood, depending on the patient. That's enough to prevent attacks. Fetal hemoglobin was seen in 58.9% to 93.6% of red blood cells.

"The longest patient is over 2 years. He's doing quite well. He's a very happy guy," said Dr. Williams.

The volunteers will be followed for a total of 15 years.

The study was financed by the National Institutes of Health.

In the second test, the initial patient with sickle cell disease stopped having the vaso-occlusive episodes that are the hallmark of the disease, according to the team led by Dr. Haydar Frangoul of the TriStar Centennial Medical Center in Nashville, Tennessee.

She and the woman with beta thalassemia were free of the need for blood transfusions after more than one year and had substantial, sustained increases in fetal hemoglobin.

Two additional sickle cell patients have also been given the treatment, known as CTX001, as have six other patients with beta thalassemia. The researchers said all have improved.

That test was financed and designed by CRISPR Therapeutics and Vertex Pharmaceuticals. The companies hope to enroll 45 patients suffering from each disease.

With several research teams working on gene therapy techniques, "I suspect that a (sickle cell) treatment like this will probably become available in five years," Dr. Williams predicted.

The cost-effectiveness of the treatment has not been determined.

Dr. Williams said an estimated $3 billion is spent on caring for sickle cell patients each year. That includes frequent hospitalizations but not other factors such as job loss, education disruption and shortened lifespan.

"So even though this may be an expensive treatment, to the extent that it mitigates patient complications and suffering, this is value-added," he said.

"It's a patient population that, over the decades, has been underserved," said Dr. Esrick, who like Dr. Williams is on the faculty of Harvard Medical School.

Both sickle cell disease and beta thalassemia can be cured with a bone marrow transplant, but only 20% of people with those conditions have someone who can donate marrow.

SOURCES: https://bit.ly/2LbUEDb and https://bit.ly/2Jv9jZL The New England Journal of Medicine, online December 5, 2020.

By Gene Emery

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