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Development of allele-specific therapeutic siRNA for keratin 5 mutations in epidermolysis bullosa simplex.
[epidermolysis bullosa simplex]
Epidermolysis
bullosa
simplex
(
EBS
)
is
an
incurable
,
inherited
skin
-blistering
disorder
predominantly
caused
by
dominant-negative
mutations
in
the
genes
encoding
keratins
K
5
or
K
14
.
RNA
interference
,
particularly
in
the
form
of
small
interfering
RNA
(
siRNA
)
,
offers
a
potential
therapy
route
for
EBS
and
related
keratin
disorders
by
selectively
silencing
the
mutant
allele
.
Here
,
using
a
systemic
screening
system
based
on
a
luciferase
reporter
gene
assay
,
we
have
developed
mutant-
specific
siRNAs
for
two
independent
EBS
-causing
missense
mutations
in
the
K
5
gene
(
p
.
Ser
181
Pro
and
p
.
Asn
193
Lys
)
.
The
specificity
of
the
allele-
specific
inhibitors
identified
in
the
screen
was
subsequently
confirmed
at
the
protein
level
,
where
the
lead
inhibitors
were
shown
to
strongly
knock
down
the
expression
of
mutant
proteins
with
negligible
effect
on
wild-
type
K
5
expression
.
In
a
cell-based
model
system
,
the
lead
inhibitors
were
able
to
significantly
reverse
the
cytoskeletal
aggregation
phenotype
.
Overall
,
this
approach
shows
promise
for
the
treatment
of
EBS
and
paves
the
way
for
future
clinical
trials
.
Diseases
Validation
Diseases presenting
"future clinical trials"
symptom
alexander disease
epidermolysis bullosa simplex
erythropoietic protoporphyria
junctional epidermolysis bullosa
krabbe disease
proteus syndrome
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