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Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.
[x-linked adrenoleukodystrophy]
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
,
the
most
common
peroxisomal
disorder
,
is
a
clinically
heterogeneous
disease
that
can
manifest
as
devastating
inflammatory
cerebral
demyelination
(
CALD
)
leading
to
death
of
affected
males
.
Currently
,
the
only
curative
treatment
is
allogeneic
hematopoietic
stem
cell
transplantation
(
HSCT
)
.
However
,
HSCT
is
only
effective
when
performed
at
an
early
stage
because
the
inflammation
may
progress
for
eighteen
months
after
HSCT
.
Thus
,
alternative
treatment
options
able
to
immediately
halt
the
progression
are
urgently
needed
.
X-
ALD
is
caused
by
mutations
in
the
ABCD
1
gene
,
encoding
the
peroxisomal
membrane
protein
ABCD
1
,
resulting
in
impaired
very
long
-chain
fatty
acid
metabolism
.
The
related
ABCD
2
protein
is
able
to
functionally
compensate
for
ABCD
1
-
deficiency
both
in
vitro
and
in
vivo
.
Recently
,
we
demonstrated
that
of
the
cell
types
derived
from
CD
34
+
stem
cells
,
predominantly
monocytes
but
not
lymphocytes
are
metabolically
impaired
in
X-
ALD
.
As
ABCD
2
is
virtually
not
expressed
in
these
cells
,
we
hypothesize
that
a
pharmacological
up-regulation
of
ABCD
2
should
compensate
metabolically
and
halt
the
inflammation
in
CALD
.
Retinoids
are
anti-
inflammatory
compounds
known
to
act
on
ABCD
2
.
Here
,
we
investigated
the
capacity
of
selected
retinoids
for
ABCD
2
induction
in
human
monocytes
/
macrophages
.
In
THP-
1
cells
,
13
-
cis-retinoic
acid
reached
the
highest
,
fivefold
,
increase
in
ABCD
2
expression
.
To
test
the
efficacy
of
retinoids
in
vivo
,
we
analyzed
ABCD
2
mRNA
levels
in
blood
cells
isolated
from
acne
patients
receiving
13
-
cis-retinoic
acid
therapy
.
In
treated
acne
patients
,
ABCD
2
mRNA
levels
were
comparable
to
pre-treatment
levels
in
monocytes
and
lymphocytes
.
Nevertheless
,
when
primary
monocytes
were
in
vitro
differentiated
into
macrophages
and
treated
with
13
-
cis-retinoic
acid
,
we
observed
a
fourfold
induction
of
ABCD
2
.
However
,
the
level
of
ABCD
2
induction
obtained
by
retinoids
alone
is
probably
not
of
therapeutic
relevance
for
X-
ALD
.
In
conclusion
,
our
results
suggest
a
change
in
promoter
accessibility
during
macrophage
differentiation
allowing
induction
of
ABCD
2
by
retinoids
.
Diseases
Validation
Diseases presenting
"inflammatory compounds"
symptom
x-linked adrenoleukodystrophy
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