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Encouraging Results Seen with Novel Approach to Gene Therapy for Sickle Cell Disease

Study validates BCL11A as therapeutic target in SCD

(Orlando, FL, Dec. 10, 2019) — Three adult patients with sickle cell disease (SCD) are doing well after receiving an infusion of their own stem cells that had been genetically engineered to induce them to stop producing harmful “sickle” hemoglobin and start producing a healthy form of hemoglobin, according to a study presented today during the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando.

The three patients, who are now 18, 10, and nine months post-infusion, are producing significantly increased amounts of the healthy form of hemoglobin and have so far shown no therapy-related adverse effects beyond those expected with autologous hematopoietic stem cell transplantation, said senior author David A. Williams, MD, chief scientific officer at Boston Children’s Hospital.

“We are very encouraged by the results we are seeing with this scientifically innovative approach to gene therapy for SCD,” Dr. Williams said. “This approach builds on basic research findings developed at Boston Children’s Hospital and may open the door to curative therapy for many individuals with SCD.”

SCD is the most common inherited red blood cell disorder in the United States, affecting an estimated 100,000 African Americans. In people with SCD, the red blood cells, which are normally round, become crescent or sickle shaped. As these cells travel through the bloodstream, they can get stuck, cutting off blood flow and causing intense pain. People with SCD suffer from an array of physical complications, including acute pain crises, joint and organ damage, stroke, and reduced life expectancy. 

Currently, the only established cure for SCD is a transplant of healthy stem cells from a matched sibling donor. However, many patients with SCD do not have a suitable sibling donor and some stem cell transplants have significant complications or fail. Gene therapy is an alternative approach that uses the patient’s own stem cells and does not rely on the availability of a compatible donor.

Before birth and during the first weeks of life, human infants produce a special form of hemoglobin, a protein in red blood cells that is responsible for transporting oxygen throughout the body. This so-called fetal hemoglobin is particularly well-suited for the lower oxygen environment present in the womb, and researchers have long recognized that it inhibits the formation of sickled red blood cells. Shortly after birth, however, infants gradually stop producing fetal hemoglobin. It is replaced by adult hemoglobin that, in people with SCD, is prone to sickling. Pre-clinical research from Boston Children’s Hospital has shown that suppressing the action of a protein known as BCL11A can reverse SCD by reactivating the production of fetal hemoglobin.

In this study, Dr. Williams and his collaborators devised a technique to genetically engineer an inactivated virus to deliver genetic instructions to drastically reduce the expression of BCL11A in red blood cells, using the cell’s own machinery called a microRNA. The key feature of the new approach is targeting BCL11A with a structure they named a shmiR. This “flips the switch” back to a fetal hemoglobin in the red cells. 

Patients are first treated with a single injection of a drug that causes stem cells to move from the bone marrow into the blood vessels. Next, a machine extracts the stem cells from the blood and returns the remaining blood cells to the patient. The stem cells are then sent to a laboratory where they are transduced with the inactivated virus carrying the instructions to reduce BCL11A expression. The gene-modified cells are then frozen while safety testing is performed on them.

In the final phase of treatment, the patient is admitted to the transplant unit and treated with a drug that eliminates the existing blood-forming stem cells in the bone marrow to make space in the bone marrow for the transplanted stem cells. Then the gene-modified stem cells are thawed and given back to the patient by intravenous infusion. The patient remains in the hospital for several weeks until engraftment occurs, which means that the body has accepted the new stem cells and the stem cells have begun to produce new blood and immune-system cells. 

Post-treatment follow-up shows that all three adult patients now have normal or near-normal hemoglobin levels and are producing fetal hemoglobin in quantities that should be sufficient to prevent sickling of red blood cells, Dr. Williams said. One patient continues to receive planned blood transfusions due to extensive pre-existing blood vessel damage in the brain to reduce any risk of stroke, but now needs fewer transfusions than before receiving the investigational gene therapy.

“We are seeing a remarkable reproducibility of the treatment effect in all of the patients treated to date,” said Dr. Williams. “The treatment also appears to be durable, with the first patient now 18 months out.”

In addition to the three adult patients, ranging from 21-26 years of age, data for two adolescents ages 16 and 12 years who have also received the gene therapy will be reviewed. At five months and one-month post-treatment, these patients are so far showing similar outcomes. For all patients, the hope is that increasing fetal hemoglobin levels enough to prevent sickling will decrease their long-term risk for complications of SCD such as organ damage, strokes, and lung disease, he said. 

Patients will be followed for 15 years, as recommended by the U.S. Food and Drug Administration for recipients of gene therapy. The researchers are currently in discussions with the National Institutes of Health, which is funding the study, to make the investigational gene therapy available to a larger number of patients by expanding the number of sites that can offer it.

bluebird bio in Cambridge, Mass, has provided technical support and resources for the program.

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on VTE, sickle cell disease, inclusive medicine, and CAR-T and beyond. For the complete annual meeting program and abstracts, visit www.hematology.org/annual-meeting. Follow @ASH_hematology and #ASH19 on Twitter and like ASH on Facebook for the most up-to-date information about the 2019 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH publishes Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online. In 2016, ASH launched Blood Advances (www.bloodadvances.org), an online, peer-reviewed open-access journal.