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A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice.
[canavan disease]
Canavan
's
disease
(
CD
)
is
a
fatal
pediatric
leukodystrophy
caused
by
mutations
in
aspartoacylase
(
AspA
)
gene
.
Currently
,
there
is
no
effective
treatment
for
CD
;
however
,
gene
therapy
is
an
attractive
approach
to
ameliorate
the
disease
.
Here
,
we
studied
progressive
neuropathology
and
gene
therapy
in
short
-lived
(
≤
1
month
)
AspA
(
-
/
-
)
mice
,
a
bona
-fide
animal
model
for
the
severest
form
of
CD
.
Single
intravenous
(
IV
)
injections
of
several
primate
-derived
recombinant
adeno-associated
viruses
(
rAAVs
)
as
late
as
postnatal
day
20
(
P
20
)
completely
rescued
their
early
lethality
and
alleviated
the
major
disease
symptoms
,
extending
survival
in
P
0
-
injected
rAAV
9
and
rAAVrh
8
groups
to
as
long
as
2
years
thus
far
.
We
successfully
used
microRNA
(
miRNA
)
-
mediated
post-transcriptional
detargeting
for
the
first
time
to
restrict
therapeutic
rAAV
expression
in
the
central
nervous
system
(
CNS
)
and
minimize
potentially
deleterious
effects
of
transgene
overexpression
in
peripheral
tissues
.
rAAV
treatment
globally
improved
CNS
myelination
,
although
some
abnormalities
persisted
in
the
content
and
distribution
of
myelin-
specific
and
-
enriched
lipids
.
We
demonstrate
that
systemically
delivered
and
CNS-
restricted
rAAVs
can
serve
as
efficacious
and
sustained
gene
therapeutics
in
a
model
of
a
severe
neurodegenerative
disorder
even
when
administered
as
late
as
P
20
.
