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Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity.
[wiskott-aldrich syndrome]
Wiskott-
Aldrich
syndrome
(
WAS
)
is
characterized
by
microthrombocytopenia
,
immunodeficiency
,
autoimmunity
,
and
susceptibility
to
malignancies
.
In
our
hematopoietic
stem
cell
gene
therapy
(
GT
)
trial
using
a
γ-retroviral
vector
,
9
of
10
patients
showed
sustained
engraftment
and
correction
of
WAS
protein
(
WASP
)
expression
in
lymphoid
and
myeloid
cells
and
platelets
.
GT
resulted
in
partial
or
complete
resolution
of
immunodeficiency
,
autoimmunity
,
and
bleeding
diathesis
.
Analysis
of
retroviral
insertion
sites
revealed
>
140
,
000
unambiguous
integration
sites
and
a
polyclonal
pattern
of
hematopoiesis
in
all
patients
early
after
GT
.
Seven
patients
developed
acute
leukemia
[
one
acute
myeloid
leukemia
(
AML
)
,
four
T
cell
acute
lymphoblastic
leukemia
(
T-
ALL
)
,
and
two
primary
T-
ALL
with
secondary
AML
associated
with
a
dominant
clone
with
vector
integration
at
the
LMO
2
(
six
T-
ALL
)
,
MDS
1
(
two
AML
)
,
or
MN
1
(
one
AML
)
locus
]
.
Cytogenetic
analysis
revealed
additional
genetic
alterations
such
as
chromosomal
translocations
.
This
study
shows
that
hematopoietic
stem
cell
GT
for
WAS
is
feasible
and
effective
,
but
the
use
of
γ-retroviral
vectors
is
associated
with
a
substantial
risk
of
leukemogenesis
.
Diseases
Validation
Diseases presenting
"immunodeficiency"
symptom
adrenal incidentaloma
allergic bronchopulmonary aspergillosis
cushing syndrome
dracunculiasis
hirschsprung disease
hodgkin lymphoma, classical
homocystinuria without methylmalonic aciduria
kabuki syndrome
legionellosis
malignant atrophic papulosis
oculocutaneous albinism
omenn syndrome
papillon-lefèvre syndrome
primary effusion lymphoma
primary hyperoxaluria type 1
pyomyositis
severe combined immunodeficiency
sneddon syndrome
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated