Encouraging Results Seen with Novel Approach to Gene Therapy for Sickle Cell Disease
validates BCL11A as therapeutic target in SCD
Published on: December 10, 2019
(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.
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.
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.”
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.
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.
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. Preclinical 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.
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.
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.
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
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
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.”
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
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.
Adam Silverstein, FleishmanHillard
Leah Enser, ASH
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