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Effective clearance of GL-3 in a human iPSC-derived cardiomyocyte model of Fabry disease.
[fabry disease]
Fabry
disease
,
a
rare
X-
linked
α-galactosidase
A
deficiency
,
causes
progressive
lysosomal
accumulation
of
globotriaosylceramide
(
GL-
3
)
in
a
variety
of
cell
types
.
As
the
disease
progresses
,
renal
failure
,
left
ventricular
hypertrophy
,
and
strokes
may
occur
.
Enzyme
replacement
therapy
(
ERT
)
,
with
recombinant
α-galactosidase
A
,
is
currently
available
for
use
to
reduce
GL-
3
deposits
.
However
,
although
it
improves
cardiac
function
and
decreases
left
ventricular
mass
,
GL-
3
clearance
upon
ERT
has
been
demonstrated
in
cardiac
capillary
endothelium
but
not
in
cardiomyocytes
of
patients
.
Relevant
models
are
needed
to
understand
the
pathogenesis
of
cardiac
disease
and
explore
new
therapeutic
approaches
.
We
generated
induced
pluripotent
stem
cells
(
iPSC
)
from
Fabry
patients
and
differentiated
them
into
cardiomyocytes
.
In
these
cells
,
GL-
3
accumulates
in
the
lysosomes
over
time
,
resulting
in
phenotypic
changes
similar
to
those
found
in
cardiac
tissue
from
Fabry
patients
.
Using
this
human
in
vitro
model
,
we
demonstrated
that
substrate
reduction
therapy
via
glucosylceramide
synthase
inhibition
was
able
to
prevent
accumulation
and
to
clear
lysosomal
GL-
3
in
cardiomyocytes
.
This
new
in
vitro
model
recapitulates
essential
features
of
cardiomyocytes
from
patients
with
Fabry
disease
and
therefore
provides
a
useful
and
relevant
tool
for
further
investigations
of
new
therapy
.
Diseases
Validation
Diseases presenting
"progressive lysosomal accumulation"
symptom
fabry disease
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