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AAV-mediated gene delivery in adult GM1-gangliosidosis mice corrects lysosomal storage in CNS and improves survival.
[gm1 gangliosidosis]
GM
1
-
gangliosidosis
is
a
glycosphingolipid
(
GSL
)
lysosomal
storage
disease
caused
by
a
genetic
deficiency
of
acid
β-galactosidase
(
βgal
)
,
which
results
in
the
accumulation
of
GM
1
-
ganglioside
and
its
asialo-form
(
GA
1
)
primarily
in
the
CNS
.
Age
of
onset
ranges
from
infancy
to
adulthood
,
and
excessive
ganglioside
accumulation
produces
progressive
neurodegeneration
and
psychomotor
retardation
in
humans
.
Currently
,
there
are
no
effective
therapies
for
the
treatment
of
GM
1
-
gangliosidosis
.
In
this
study
we
examined
the
effect
of
thalamic
infusion
of
AAV
2
/
1
-
βgal
vector
in
adult
GM
1
mice
on
enzyme
distribution
,
activity
,
and
GSL
content
in
the
CNS
,
motor
behavior
,
and
survival
.
Six
to
eight
week
-old
GM
1
mice
received
bilateral
injections
of
AAV
vector
in
the
thalamus
,
or
thalamus
and
deep
cerebellar
nuclei
(
DCN
)
with
pre-determined
endpoints
at
1
and
4
months
post-injection
,
and
the
humane
endpoint
,
or
52
weeks
of
age
.
Enzyme
activity
was
elevated
throughout
the
CNS
of
AAV-treated
GM
1
mice
and
GSL
storage
nearly
normalized
in
most
structures
analyzed
,
except
in
the
spinal
cord
which
showed
∼
50
%
reduction
compared
to
age-matched
untreated
GM
1
mice
spinal
cord
.
Survival
was
significantly
longer
in
AAV-treated
GM
1
mice
(
52
wks
)
than
in
untreated
mice
.
However
the
motor
performance
of
AAV-treated
GM
1
mice
declined
over
time
at
a
rate
similar
to
that
observed
in
untreated
GM
1
mice
.
Our
studies
show
that
the
AAV-modified
thalamus
can
be
used
as
a
'
built-
in
'
central
node
network
for
widespread
distribution
of
lysosomal
enzymes
in
the
mouse
cerebrum
.
In
addition
,
this
study
indicates
that
thalamic
delivery
of
AAV
vectors
should
be
combined
with
additional
targets
to
supply
the
cerebellum
and
spinal
cord
with
therapeutic
levels
of
enzyme
necessary
to
achieve
complete
correction
of
the
neurological
phenotype
in
GM
1
mice
.
Diseases
Validation
Diseases presenting
"a genetic deficiency of acid β-galactosidase"
symptom
gm1 gangliosidosis
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