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Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice.
[classical phenylketonuria]
Classical
phenylketonuria
(
PKU
)
is
a
metabolic
disorder
caused
by
a
deficiency
of
the
hepatic
enzyme
phenylalanine
hydroxylase
(
PAH
)
.
If
untreated
,
accumulation
of
phenylalanine
will
damage
the
developing
brain
of
affected
individuals
,
leading
to
severe
mental
retardation
.
Here
,
we
show
that
a
liver
-directed
PAH
gene
transfer
brought
about
long
-term
correction
of
hyperphenylalaninemia
and
behavioral
improvement
in
a
mouse
model
of
PKU
.
A
recombinant
adeno-associated
virus
(
AAV
)
vector
carrying
the
murine
PAH
cDNA
was
constructed
and
administered
to
PAH
-
deficient
mice
(
strain
PAH
(
enu
2
)
)
via
the
portal
vein
.
Within
2
weeks
of
treatment
,
the
hyperphenylalaninemic
phenotype
improved
and
completely
normalized
in
the
animals
treated
with
higher
vector
doses
.
The
therapeutic
effect
persisted
for
40
weeks
in
male
mice
,
while
serum
phenylalanine
concentrations
in
female
animals
gradually
returned
to
pretreatment
levels
.
Notably
,
this
long
-term
correction
of
hyperphenylalaninemia
was
associated
with
a
reversal
of
hypoactivity
observed
in
PAH
(
enu
2
)
mice
.
While
locomotory
activity
over
24
h
and
exploratory
behavior
were
significantly
decreased
in
untreated
PAH
(
enu
2
)
mice
compared
with
the
age-matched
controls
,
these
indices
were
completely
normalized
in
12
-
month
-old
male
PKU
mice
with
lowered
serum
phenylalanine
.
These
results
demonstrate
that
AAV-mediated
liver
transduction
ameliorated
the
PKU
phenotype
,
including
central
nervous
system
dysfunctions
.