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A high-throughput screening assay using Krabbe disease patient cells.
[krabbe disease]
Globoid
cell
leukodystrophy
(
GLD
)
or
Krabbe
disease
is
a
lysosomal
disease
caused
by
β-galactocerebrosidase
(
GALC
)
deficiency
resulting
in
a
rapidly
progressive
neurodegenerative
disorder
.
Unfortunately
,
the
only
available
treatment
is
hematopoietic
bone
marrow
transplantation
,
which
prevents
its
fulminant
manifestation
but
without
treating
further
neurological
manifestations
.
Here
,
we
describe
the
development
of
a
cellular
high
-throughput
screening
(
HTS
)
assay
using
GLD
patient
fibroblasts
to
screen
for
small
molecules
that
enhance
the
residual
mutant
GALC
enzymatic
activity
.
Small
molecules
have
substantial
therapeutic
potential
in
GLD
because
they
are
more
prone
to
cross
the
blood
-
brain
barrier
,
reaching
the
neuronal
affected
cells
.
The
transformation
of
primary
skin
fibroblasts
with
SV
40
large
T
antigen
has
been
shown
to
maintain
the
biochemical
characteristics
of
the
GLD
cells
and
generates
sufficient
cells
for
the
HTS
.
Using
a
specific
fluorescent
substrate
,
residual
GALC
activity
from
an
SV
40
-
transformed
GLD
patient
fibroblast
was
measurable
in
high
-density
microplates
.
The
pilot
quantitative
HTS
against
a
small
compound
collection
showed
robust
statistics
.
The
small
molecules
that
showed
active
concentration-response
curves
were
further
studied
in
primary
GLD
fibroblasts
.
This
cell-based
HTS
assay
demonstrates
the
feasibility
of
employing
live
GLD
patient
cells
to
identify
therapeutic
agents
that
can
potentially
be
used
for
the
treatment
of
this
progressive
neurodegenerative
disease
.
Diseases
Validation
Diseases presenting
"skin fibroblasts"
symptom
child syndrome
cowden syndrome
cystinuria
dentinogenesis imperfecta
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
gm1 gangliosidosis
homocystinuria without methylmalonic aciduria
krabbe disease
malignant atrophic papulosis
monosomy 21
neonatal adrenoleukodystrophy
pyruvate dehydrogenase deficiency
werner syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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