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Bone marrow transplantation increases efficacy of central nervous system-directed enzyme replacement therapy in the murine model of globoid cell leukodystrophy.
[krabbe disease]
Globoid
cell
leukodystrophy
(
GLD
,
Krabbe
disease
)
,
is
an
autosomal
recessive
,
neurodegenerative
disease
caused
by
the
deficiency
of
the
lysosomal
enzyme
galactocerebrosidase
(
GALC
)
.
In
the
absence
of
GALC
,
the
toxic
metabolite
psychosine
accumulates
in
the
brain
and
causes
the
death
of
the
myelin-producing
cells
,
oligodendrocytes
.
Currently
,
the
only
therapy
for
GLD
is
hematopoietic
stem
cell
transplantation
using
bone
marrow
(
BMT
)
or
umbilical
cord
blood
.
However
,
this
is
only
partially
effective
.
Previous
studies
have
shown
that
enzyme
replacement
therapy
(
ERT
)
provides
some
therapeutic
benefit
in
the
murine
model
of
GLD
,
the
Twitcher
mouse
.
Experiments
have
also
shown
that
two
disparate
therapies
can
produce
synergistic
effects
when
combined
.
The
current
study
tests
the
hypothesis
that
BMT
will
increase
the
therapeutic
effects
of
ERT
when
these
two
treatments
are
combined
.
Twitcher
mice
were
treated
with
either
ERT
alone
or
both
ERT
and
BMT
during
the
first
2
-
4
days
of
life
.
Recombinant
enzyme
was
delivered
by
intracerebroventricular
(
ICV
)
and
intrathecal
(
IT
)
injections
.
Twitcher
mice
receiving
ERT
had
supraphysiological
levels
of
GALC
activity
in
the
brain
24
h
after
injection
.
At
36
days
of
age
,
ERT-treated
Twitcher
mice
had
reduced
psychosine
levels
,
reduced
neuroinflammation
,
improved
motor
function
,
and
increased
lifespan
.
Twitcher
mice
receiving
both
ERT
and
BMT
had
significantly
increased
lifespan
,
improved
motor
function
,
reduced
psychosine
levels
,
and
reduced
neuroinflammation
in
certain
areas
of
the
brain
compared
to
untreated
or
ERT-treated
Twitcher
mice
.
Together
,
these
results
indicate
that
BMT
enhances
the
efficacy
of
ERT
in
GLD
.
Diseases
Validation
Diseases presenting
"leukodystrophy"
symptom
achondroplasia
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
carcinoma of the gallbladder
classical phenylketonuria
coats disease
fabry disease
gm1 gangliosidosis
krabbe disease
neonatal adrenoleukodystrophy
phenylketonuria
pyruvate dehydrogenase deficiency
wiskott-aldrich syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated