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Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy.
[krabbe disease]
Globoid
cell
leukodystrophy
(
GLD
;
also
known
as
Krabbe
disease
)
is
an
invariably
fatal
lysosomal
storage
disorder
caused
by
mutations
in
the
galactocerebrosidase
(
GALC
)
gene
.
Hematopoietic
stem
cell
(
HSC
)
-
based
gene
therapy
is
being
explored
for
GLD
;
however
,
we
found
that
forced
GALC
expression
was
toxic
to
HSCs
and
early
progenitors
,
highlighting
the
need
for
improved
regulation
of
vector
expression
.
We
used
a
genetic
reporter
strategy
based
on
lentiviral
vectors
to
detect
microRNA
activity
in
hematopoietic
cells
at
single
-cell
resolution
.
We
report
that
miR-
126
and
miR-
130
a
were
expressed
in
HSCs
and
early
progenitors
from
both
mice
and
humans
,
but
not
in
differentiated
progeny
.
Moreover
,
repopulating
HSCs
could
be
purified
solely
on
the
basis
of
miRNA
expression
,
providing
a
new
method
relevant
for
human
HSC
isolation
.
By
incorporating
miR-
126
target
sequences
into
a
GALC
-expressing
vector
,
we
suppressed
GALC
expression
in
HSCs
while
maintaining
robust
expression
in
mature
hematopoietic
cells
.
This
approach
protected
HSCs
from
GALC
toxicity
and
allowed
successful
treatment
of
a
mouse
GLD
model
,
providing
a
rationale
to
explore
HSC-based
gene
therapy
for
GLD
.
Diseases
Validation
Diseases presenting
"highlighting the need for improved regulation of vector expression"
symptom
krabbe disease
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