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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
"active concentration-response curves"
symptom
krabbe disease
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