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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
"acute lymphoblastic leukemia"
symptom
classical phenylketonuria
cystinuria
hodgkin lymphoma, classical
monosomy 21
oculocutaneous albinism
pyomyositis
severe combined immunodeficiency
wiskott-aldrich syndrome
This symptom has already been validated