Gene Therapy for “Bubble Boy” Disease Appears to be Effective and Safe
October 09, 2014
new form of gene therapy for boys with
“bubble boy” disease appears to be not only effective but also may avoid the
late-developing leukemia seen in a quarter of SCID-X1 patients in pioneering
gene therapy trials in Europe more than a decade ago.
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Promising early success
and safety results from international gene therapy trial for "bubble
boy" disease reported in New England Journal of Medicine
Data raise hopes for
approach's long-term safety after earlier trial led to leukemia in one-quarter
(October 9, 2014)
– A new form of gene therapy for boys with
X-linked severe combined immunodeficiency syndrome (SCID-X1), a life-threatening
condition also known as “bubble boy” disease, appears to be both effective and safe,
according to a collaborative research team from Dana-Farber/Boston Children's Cancer and
Blood Disorders Center and other institutions conducting an international clinical
trial. Early data suggest that the therapy may avoid the late-developing leukemia
seen in a quarter of SCID-X1 patients in pioneering gene therapy trials in
Europe more than a decade ago.
of nine boys recruited to date onto the trial are alive between 12 and 38
months after treatment, with no SCID-X1-associated infections, the research
team reported today in the New England
Journal of Medicine. Gene therapy alone generated functioning immune
systems in seven of the eight. Genetic studies of the boys’ new T-cells, which
are critical components of the body’s immune system, reveal that the viral
vector used to deliver the gene therapy did not lead to an expansion of cells
with vector insertions near known cancer-causing genes, raising cautious hopes
about the vector's long-term safety. One child died of an overwhelming infection
present at the time gene therapy began. Left untreated, boys with SCID-X1
usually die of infection before their first birthday.
investigators will continue to monitor the patients for any signs of treatment-related
leukemia for 15 years. In the prior European trials—which were the first to
demonstrate gene therapy’s potential to successfully cure a disease—leukemia appeared
two to five years after treatment. This outcome was one of several events that
together slowed clinical progress in gene therapy for many years.
modified vector created for the current trial is a self-inactivating gammaretrovirus,
designed to deliver its payload effectively while minimizing the chance of
inadvertently turning on genes, called oncogenes, that could lead to leukemia.
goal was to take the molecular data from the prior trial and use it to produce
a vector that would remain effective and at the same time reduce the risk of
leukemia," said David A. Williams, MD, a leader of
Dana-Farber/Boston Children's, chief of the Division of Hematology/Oncology and
director of clinical and translational research at Boston Children’s Hospital,
principal investigator for the gene therapy trial's U.S. sites, and corresponding
senior author of the NEJM paper.
"The efficacy data from our study is clear: The vector does work to
correct the disease. And by a surrogate endpoint, we have improved the
treatment's safety, although it's too early to say that we've completely
eliminated the long-term risk of leukemia."
a single round of treatment, six of the seven boys for whom the gene therapy
was successful had achieved the trial's primary efficacy endpoints—a T-cell
count greater than 300 cells per microliter of blood and T-cell proliferation
in response to stimulation with phytohemagglutinin (a test used to measure
T-cells' ability to react to pathogens). The seventh boy received a second
round of gene therapy and remains healthy despite having relatively low T-cell
counts. The eighth surviving patient was successfully treated with a conventional
hematopoietic (blood-forming) stem cell transplant after gene therapy failed to
stimulate T-cell production.
a minority of babies with SCID-X1 have the optimal donor for standard
transplant, a brother or sister who is tissue-type matched,” said co-lead
author Sung-Yun Pai, MD, a pediatric hematologist/oncologist at
Dana-Farber/Boston Children’s. “For the rest, gene therapy is a therapeutic
option that avoids the need to find an alternative donor and avoids
complications of allogeneic transplant such as graft-versus-host-disease.”
core question of the trial was whether the new self-inactivating viral vector
could safely and successfully shuttle a gene called the IL-2 receptor gamma
(IL2RG) subunit into the patients' hematopoietic stem cells. In boys born with
SCID-X1, mutations render the IL2RG gene inactive, robbing the children of the
ability to produce a functional immune system.
In addition to Dana-Farber/Boston Children’s, Necker Children’s Hospital
(Paris), Great Ormond Street Hospital (London), Cincinnati Children’s Hospital
Medical Center (Cincinnati) and UCLA Mattel Children’s Hospital (Los Angeles)
are participating in the international clinical trial.
represents the best in collaborative efforts from a number of the leading gene
therapy centers world-wide that allowed us to accomplish its goals in a
relatively short period of time,” Williams said. “The success of the trial was also
critically dependent on funding from the National Institutes of Health.”
PharmD, PhD, of Necker-Enfants Malades Hospital is co-lead author of the study,
and Alain Fischer, MD, PhD, also of Necker-Enfants Malades Hospital, is
co-corresponding senior author. Additional senior authors are: Frederic D. Bushman,
PhD, of University of Pennsylvania School of Medicine; Marina Cavazzana, MD,
PhD, of Necker-Enfants Malades Hospital; Alexandra H. Filipovich, MD,
of Cincinnati Children’s Hospital Medical Center; Donald B. Kohn, MD, of UCLA Mattel Children’s Hospital; Luigi
D. Notarangelo, MD, of Boston Children’s Hospital; and Adrian Thrasher, MG, BS,
PhD, of Great Ormond Street Hospital.
study was supported by the National Institute of Allergy and Infectious
Diseases (grant numbers U01AI087628 and R01AI082020), the National Heart, Lung
and Blood Institute (grant number P01HL073104), the NHLBI Production Assistance
for Cellular Therapy (PACT) program (contract number HHSN268201000009C),
Harvard Catalyst | The Harvard Clinical and Translational Science Center
(National Center for Advancing Translational Sciences grant number
UL1TR000170), the Boston Children's Hospital Department of Medicine, the Wellcome
Trust, Great Ormond Street Hospital Biomedical Research Centre, Great Ormond
Street Hospital Children’s Charity, the U.K. National Institute of Health
Research, the French Ministry of Health, the REBIRTH Cluster of Excellence at
Hannover Medical School, Germany, the European Research Council, the Boston
Children’s Hospital Department of Medicine and the Boston Children’s Hospital
Translational Research Program.