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PAPER SPOTLIGHT
Gene Therapy Proves
Promising for Children with
“Bubble Boy” Disease
Treatment of X-linked
severe combined immunodeficiency (SCID-X1),
a rare immune disorder
also known as “bubble boy
disease,” often involves
stem cell transplantation
from a matched sibling or
unrelated donor to replace
the patient’s diseased
stem cells with healthy
donor cells. In the absence
of a fully matched stem
cell donor, children with
SCID-X1 may receive a
transplant from a partial,
or “half-matched,” donor.
Patients may also benefit
from a completely different approach – gene
therapy.
Children with SCID-X1
are born with a genetic
defect that prevents them
from developing a normal
immune system, char-
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ASH Clinical News
acterized by a complete
block in the development
of T cells. Because they
are prone to life-threatening infections, infants
with SCID-X1 must be kept
in a sterile, protective
bubble and require extensive treatment for survival
beyond infancy.
Gene therapy involves
extracting an infant’s own
bone marrow, using a virus
to replace faulty genetic
material with a correct
copy, and then giving “corrected” bone marrow back
to the patient. While this
approach has been effective in correcting the T-cell
immunodeficiency associated with SCID-X1, there
have been no comparisons
of outcomes with gene
therapy and half-matched
stem cell transplantation.
In a retrospective study,
investigators retrospectively analyzed and compared clinical outcomes
and immune reconstitution in SCID-X1 patients
who had undergone HLAmismatched HSCT or gene
therapy. Fabien Touzot,
MD, PhD, and colleagues
found that patients
receiving gene therapy
had fewer infections and
hospitalizations than
those receiving partially
matched stem cells.
“Over the last decade,
gene therapy has emerged
as a viable alternative to a
partial matched stem cell
transplant for infants with
SCID-X1,” said Dr. Touzot,
from Necker Children’s
Hospital in Paris, France.
“To ensure that we are
providing the best alterna-
through mechanisms like
graft-versus-host disease.
In this study, seven
patients in the transplant
group had immune complications that required
immunosuppressive
therapy and further delayed immune reconstitution. And, even when Dr.
Touzot and investigators
excluded patients with
graft failure (9 patients),
they still observed a tendency toward faster T-cell
compartment development in patients treated
with gene therapy.
The more rapid reconstitution of the immune
system in patients who
received gene therapy
was also associated with
faster resolution of some
opportunistic infections (11
months in the gene therapy group vs. 25.5 months
in half-matched transplant
group; p=0.029). There
were three infection-related hospitalizations in the
gene therapy group and 15
in the half-matched transplant group. The number
of days of infection-related
hospitalization was greater
in the half-matched transplant group versus the
gene therapy group (0.04
days vs. 0.03 days per patient per year; p=0.001).
“Our analysis suggests
that gene therapy can
put these incredibly sick
children on the road to
defending themselves
against infection faster
than a half-matched
transplant,” Dr. Touzot
said. “These results suggest that, for patients
without a fully matched
stem cell donor, gene
therapy is the next-best
approach.”
Reference
Touzot F, Moshous D, Creidy R, et al. Faster
T-cell development following gene therapy
compared to haplo-identical hematopoietic
stem cell transplantation in the treatment of
SCID-X1. Blood. 2015 April 13. [Epub ahead
of print]
May 2015
NYPL/Science Source/Getty Images
David Vetter, known as “the
boy in the bubble,” was born
with SCID-X1. He is seen here
in his germ-free shell, visited
by his immunologist in 1983.
tive therapy possible,
we wanted to compare
outcomes between infants
treated with gene therapy
and infants receiving partial matched transplants.”
Dr. Touzot and colleagues studied the medical records of 27 children
diagnosed with SCID-X1
between March 1999
and December 2013; 13
patients received partialmatched transplant and
14 received gene therapy.
Patients were followed
for a median of 6 and 12
years, respectively.
The researchers compared T-cell development
among patients, as well
as key clinical outcomes,
such as infe ctions and
hospitalization.
Compared with children in the half-matched
transplant group, the 14
children who underwent
gene therapy developed
healthy immune cells
faster. In fact, six months
after treatment, 11 of the
14 gene-therapy patients
(78%) had normal T-cell
count values, while only
four of the 15 transplant
patients (26%) had normal
T-cell values at that point
(p=0.02 for CD3+; p=0.05
for CD4; p=0.002 for CD8).
Gene therapy patients
also had higher levels of
CD3, CD4, and CD8 cells at
six and 12 months following treatment. The median
level of circulating regulatory CD4+ lymphocytes was
significantly higher in gene
therapy patients than in
transplant patients at last
follow-up (62/μL and 8.5/
μL, respectively; p=0.01).
In addition to providing
better clinical outcomes,
gene therapy avoids some
of the complications associated with allogeneic
transplantation, including
the limited availability
of matched donors and
the risk of graft failure,
and end-organ damage