By Roxanne Nelson

RESEARCH UPDATE

NEW GENE THERAPY POTENTIAL CURE FOR “BUBBLE BOY DISEASE”

An experimental gene therapy has allowed children with SCID-1X to develop fully functioning
immune systems

uring the 1970s and into the early

D 1980s, a Texas boy captivated the
media and public at large for his unusual
Babies born with life-threatening SCID-X1
developed functional immune
systems following an
living arrangements. Known as the “boy in experimental gene
the bubble,” David Vetter spent his entire therapy.
life inside a complex containment system
designed to protect him from the ordinary
environment that most people take for
granted. For 12 years, he remained in
one type of plastic bubble or another; he
could only be touched by hands encased
in sterile gloves, and anything given to
him, be it food, water, diapers, clothing, or
books, had to first be sterilized and then
inserted through airlocks.
David Vetter was born with X-linked

severe combined immunodeficiency, or
SCID X1, a term that applies to
the most severe form of primary
immunodeficiencies. Commonly known
as “bubble boy disease,” SCID-X1 remains
a very rare and life-threatening disorder
caused by mutations in the gene that
encodes the common g-chain (IL2RG
[GenBank accession number, D11086.1]).
SCID-X1 patients are prone to severe
bacterial, viral, or fungal infections early
in life and, if untreated, usually die within
1 year due to severe, recurrent infections.
Interventions used to restore immunity
include allogeneic hematopoietic stem
cell transplantation or autologous gene
therapy. However, study researchers now
report that 8 children with SCID-X1 have
developed fully functioning immune
systems following treatment with an
experimental gene therapy that was
developed and produced at St. Jude
Children’s Research Hospital in Memphis,
Tennessee (Mamcarz et al, 2019). This
therapy is “feasible,” notes Ewelina
Mamcarz, MD, one of the study’s lead
investigators at St. Jude. “We successfully
generated the product for all our babies
on the study, and all developed an
immune system.”
Dr. Mamcarz cautions, however, that
the study is still in a research phase and that
the current standard of care is still a matched
sibling donor transplant. Sadly, that is not an
option for most. “Less than 20% of babies
have a matched donor so the next option is
a transplant from an unrelated donor,” she
says. Transplants from alternative donors
are generally not as effective and often fail
to reconstitute immunity associated with
T cells, B cells, and natural killer (NK)
cells unless high-dose chemotherapy is
administered. In addition, autologous
gene therapy with g-retroviral vectors have
failed to reconstitute B-cell and NK-cell
© jm1366 / Shutterstock.com
immunity and are associated with vector-
related leukemia. Safety was improved with
second-generation g–retroviral vectors,
but therapy still did not restore humoral
immunity or durable NK cell production
when administered to patients without
conditioning chemotherapy.
“We will follow the patients on this
study for 10 years and then they will be
enrolled on a long-term, follow-up study
for life,” says Dr. Mamcarz. “We will follow
the patients for weaning of the immune
system, but that has not happened yet,
and our plan is to enroll more patients on
the study and follow them long term.”
The Study
The new lentiviral vector gene therapy
in combination with nonmyeloablative

1114 © 2019 Wiley Periodicals, Inc.

RESEARCH UPDATE CONTINUED
busulfan conditioning had already been
successfully used in restoring immunity
to 5 patients who had undergone an
unsuccessful allogeneic hematopoietic
stem cell transplantation for SCID-X1.
The authors hypothesized that this
combination, administered by means
of pharmacokinetic dose targeting,
would be safe and effective when used
as a primary treatment in infants with
newly diagnosed SCID-X1. To test their
hypothesis, the researchers initiated
the Lentiviral Vector SCID-X1 Newly
Diagnosed (LVXSCID-ND) dual-center,
phase 1–2 safety and efficacy trial.
Treatment was initiated at a median
age of 3.5 months in 8 newly diagnosed
SCID-X1 patients. Within this group, 5
had pre-existing infections. The cohort
was followed for a median of 16.4 months
after treatment, and no unexpected side
effects were observed. The numbers of
CD3+, CD4+, and naive CD4+ T cells and
NK cells normalized in 7 of the infants by 3
to 4 months following the infusion, but the
eighth infant initially had an insufficient
T-cell count. After receiving a boost of
gene-corrected cells without busulfan
conditioning, however, this infant’s T
cells normalized. Previous infections
resolved in all infants, and IgM levels
normalized in 7 of them. Four patients
were able to discontinue intravenous
immune globulin supplementation, with
3 achieving a response to vaccines.
“The study is an important milestone
since it shows improvement in efficacy and
safety of gene therapy for X-SCID,” says
Stephan Ehl, MD, Medical Director of the
Center for Chronic Immunodeficiency
at the Medical Center – University of
Freiburg in Germany. He points out that
although this is not the first successful
gene therapy for this disease, and there
are alternative options for therapy with
an excellent safety/risk profile, this is still
an important advance.
“It is not clear when it will be
available for clinical use, but companies
are working hard on this,” says Dr. Ehl. “In
another related disease—ADA-SCID—
gene therapy is now available for clinical use.
However, this is not the only therapy, and
we are using different options for different
children depending on a variety of factors.”
“The study is an important milestone since it
shows improvement in efficacy and safety of
gene therapy for X-SCID.”
— Stephan Ehl, MD
Gene therapy for ADA-SCID is not
the standard of care at this time. “The
long-term outcomes of gene therapy
concerning T-cell reconstitution also
depend on thymic factors, and from
the HSCT experience, there are some
limitations expected,” Dr. Ehl adds.
“However, it will take 20 years to
understand whether gene therapy offers
an advantage here.”
Legacy of the Bubble Boy
When David Vetter was born in 1971, his
diagnosis was a veritable death sentence.
The family had already lost one infant to
the disease, and the only potential cure
was a bone marrow transplant from an
exact matched donor. An exhaustive
search failed to turn up a perfectly
matched donor, and research had not
advanced far enough to allow for a less-
than-perfect match. The young man was
destined to remain inside his bubble until
another effective treatment or cure could
be found.
The case itself was fraught with
ethical dilemmas and set off a heated
debate as to whether David Vetter’s
medical team had given any consideration
to the psychological consequences of
turning this child into a research subject
(Tommasini, Magnolato & Bruno 2018).
For all intents and purposes, he was being
kept alive but essentially imprisoned in a
sterile laboratory (Lawrence 1985). Prior
to this point, “bubbles” had been used for
SCID babies for short periods, but no child
had ever been kept alive inside a bubble
for years on end. David’s parents were
hopeful that he would live long enough to
receive that elusive transplant, but as the
child grew older it became increasingly
clear that the situation could not continue
indefinitely. At one point his physicians
suggested placing him on a regimen of
gamma globulin and antibiotics and
releasing him from the bubble, but his
parents rejected the plan. Several years
later, following advances in transplanting
unmatched bone marrow, they finally
agreed that the risk was necessary.
One month after his 12th birthday,
in October 1983, David underwent
histocompatibility leukocyte antigen
(HLA)-mismatched bone marrow
transplantation from his older sister
(Simmons 1984; Sandomir 2018). There
was optimism at first, but by December, he
had begun to spike fevers and suffer from
diarrhea and vomiting. In early February,
he was removed from his bubble for the
first time in his life and placed in intensive
care. Unfortunately, screening performed
prior to David’s transplant had failed to
detect dormant Epstein-Barr virus in his
sister’s bone marrow. He died 15 days
later of Burkitt lymphoma, likely caused
by activation of the virus.
David Vetter was the last person
believed to have been confined in such a
restricted environment and, prior to his
transplant, he was the oldest survivor
of untreated SCID. Part of his legacy
provided the first conclusive evidence that
cancer can develop in a human being after
a viral infection.
References
Mamcarz E, Zhou S, Lockey T, et al. 2019.
Lentiviral gene therapy combined with low-dose
busulfan in infants with SCID-X1. N Engl J Med.
380:1525–1534.
Lawrence RJ. David the “Bubble Boy” and the
boundaries of the human. 1985. JAMA. 253:74–76.
Simmons K. Physicians continue to study cause(s) of
‘bubble’ boy’s death. 1984. JAMA. 251:1929–1931.
Tommasini A, Magnolato A, Bruno I. Innovation
for rare diseases and bioethical concerns: A thin
thread between medical progress and suffering.
2018. World J Clin Pediatr. 7:75–82.
DOI: 10.1002/ajmg.a.40453.
2019 Wiley Periodicals, Inc
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