New gene therapy strategy for sickle cell disease shows early promise in humans
December 01, 2018
Patient with severe disease is symptom-free after gene therapy knocks down BCL11A, restoring fetal hemoglobin production
Dana-Farber/Boston Children's Cancer and Blood Disorders Center
reports positive results treating sickle cell disease in its first patient,
using a novel gene therapy approach that induces production of fetal hemoglobin
while silencing production of the abnormal sickle form of adult hemoglobin. The
research team, led by David
A. Williams, MD, will share findings in the trial’s first patient on
Saturday, December 1, at the 60th Annual American Society of Hematology (ASH) meeting in San Diego, California.
cell disease, a mutation in the hemoglobin molecule, which carries
oxygen, distorts red blood cells into a crescent or sickle shape. This can
block red blood cells from passing through blood vessels and delivering oxygen
to organs and tissues. Symptoms include anemia, repeated pain episodes that
often require hospitalization and life-threatening organ damage.
clinical trial used a form of gene
therapy designed to knock down the expression of the BCL11A gene to allow production of high levels of fetal
hemoglobin. The first patient, a 21-year-old male who previously required
monthly blood transfusions, is symptom-free, has significantly increased levels
of fetal hemoglobin, and has no demonstrable sickled cells in his blood.
Researchers now plan to treat additional patients between ages 3 and 40 in the ongoing
Most people gradually stop making fetal hemoglobin shortly after
birth, its production blocked by BCL11A. While most then switch to making
healthy adult hemoglobin, people with sickle cell disease transition to making
a mutated, sickled hemoglobin.
It’s been known for many years that people’s ability to produce fetal
hemoglobin after birth can reduce the severity of their sickle cell disease.
This clinical trial, however, marks the first clinical data from an approach
targeting BCL11A as a strategy to
increase fetal hemoglobin.
“Our gene therapy approach is unique in that it leverages the
physiology of the hemoglobin switch to simultaneously increase fetal hemoglobin,
which does not sickle, and directly reduce sickling hemoglobin. Other gene
therapy trials for sickle cell disease are adding genes that encode fetal
hemoglobin or corrected, non-sickling adult hemoglobin, without directly targeting the fetal switch of the sickle hemoglobin gene,” says Williams, president of
Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Chief
Scientific Officer and Senior Vice President of Boston Children's Hospital and
a professor at Harvard Medical School. “We
predict this strategy is a very effective way to reduce or even eliminate the sickling of cells."
“This is a successful example of collaborative bench-to-bedside
research,” adds Erica
Esrick, MD, co-principal investigator on the clinical trial and a
pediatric hematologist-oncologist at Dana-Farber/Boston Children's. “The
preclinical work leading to this study dates back several years, and was born
out of a decades-long focus on clinical and discovery-based hemoglobinopathy
research at Boston Children’s Hospital.”
Key basic research leading up to the clinical trial includes the 2008
discovery by Vijay
Sankaran, MD, PhD, and Stuart
Orkin, MD, of Dana-Farber/Boston Children’s that variations in BCL11A
expression affect levels of fetal hemoglobin. That was a clue that targeting
BCL11A could be of therapeutic interest. That approach successfully reversed
sickle cell disease in a mouse model in 2011.
In the clinical trial, the patient’s blood stem cells were collected
and exposed to a lentiviral vector containing instructions to knock down BCL11A,
but only in precursors of red blood cells. The patient then received
chemotherapy in a process called conditioning, likened to plowing a field to
make room for new seeds. Finally, the gene-modified cells were given back to
him in an intravenous infusion.
“We have collected cells from several additional patients and will be
ready for them to undergo infusions soon,” says Esrick. “It’s a very exciting
time for patients, physicians and researchers in the sickle cell disease
community, with curative approaches such as gene therapy and gene editing
showing great promise.”
Others involved in the clinical trial include study co-principal
Biffi, MD, as well as, Matthew
Heeney, MD, Leslie
Lehmann, MD, Wendy London, PhD, and John Manis, MD, at
Dana-Farber/Boston Children’s, and Maureen Achebe, MD, MPH, at Brigham and
Women’s Hospital. The vector technology developed in
Williams’s laboratory has been exclusively licensed to bluebird bio in
Cambridge, Massachusetts. Bluebird bio has also provided technical support for the program and
virus supernatant produced under GMP conditions.
trial is funded by the National Institutes of Health.
Children's Cancer and Blood Disorders Center
Children's Cancer and Blood Disorders Center – one of the nation's top pediatric cancer
centers, according to U.S. News & World Report - brings together two
internationally known research and teaching institutions that have provided
comprehensive care for pediatric oncology and hematology patients since 1947.
The Harvard Medical School affiliates share a clinical staff that delivers
inpatient care at Boston Children's Hospital and most outpatient care at
Dana-Farber Cancer Institute. Follow the Center on Twitter at @childcancercare.