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Glial promoter selectivity following AAV-delivery to the immature brain.
[canavan disease]
Recombinant
adeno-associated
virus
(
AAV
)
vectors
are
versatile
tools
for
gene
transfer
to
the
central
nervous
system
(
CNS
)
and
proof-of-concept
studies
in
adult
rodents
have
shown
that
the
use
of
cell
type
-
specific
promoters
is
sufficient
to
target
AAV-mediated
transgene
expression
to
glia
.
However
,
neurological
disorders
caused
by
glial
pathology
usually
have
an
early
onset
.
Therefore
,
modelling
and
treatment
of
these
conditions
require
expanding
the
concept
of
targeted
glial
transgene
expression
by
promoter
selectivity
for
gene
delivery
to
the
immature
CNS
.
Here
,
we
have
investigated
the
AAV-mediated
green
fluorescent
protein
(
GFP
)
expression
driven
by
the
myelin
basic
protein
(
MBP
)
or
glial
fibrillary
acidic
protein
(
GFAP
)
promoters
in
the
developing
mouse
brain
.
Generally
,
the
extent
of
transgene
expression
after
infusion
at
immature
stages
was
widespread
and
higher
than
in
adults
.
The
GFAP
promoter-driven
GFP
expression
was
found
to
be
highly
specific
for
astrocytes
following
vector
infusion
to
the
brain
of
neonates
and
adults
.
In
contrast
,
the
selectivity
of
the
MBP
promoter
for
oligodendrocytes
was
poor
following
neonatal
AAV
delivery
,
but
excellent
after
vector
injection
at
postnatal
day
10
.
To
extend
these
findings
obtained
in
naïve
mice
to
a
disease
model
,
we
performed
P
10
infusions
of
AAV-
MBP
-GFP
in
aspartoacylase
(
ASPA
)
-
deficient
mouse
mutants
presenting
with
early
onset
oligodendrocyte
pathology
.
Spread
of
GFP
expression
and
selectivity
for
oligodendrocytes
in
ASPA
-mutants
was
comparable
with
our
observations
in
normal
animals
.
Our
data
suggest
that
direct
AAV
infusion
to
the
developing
postnatal
brain
,
utilising
cellular
promoters
,
results
in
targeted
and
long
-term
transgene
expression
in
glia
.
This
approach
will
be
relevant
for
disease
modelling
and
gene
therapy
for
the
treatment
of
glial
pathology
.
Diseases
Validation
Diseases presenting
"postnatal day"
symptom
canavan disease
child syndrome
dentinogenesis imperfecta
hydrocephalus with stenosis of the aqueduct of sylvius
lamellar ichthyosis
pendred syndrome
zellweger syndrome
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