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Complete restoration of phenylalanine oxidation in phenylketonuria mouse by a self-complementary adeno-associated virus vector.
[classical phenylketonuria]
Classical
phenylketonuria
(
PKU
)
arises
from
a
deficiency
of
phenylalanine
hydroxylase
(
PAH
)
that
catalyses
phenylalanine
oxidation
in
the
liver
.
Lack
of
PAH
activity
causes
massive
hyperphenylalaninemia
and
consequently
severe
brain
damage
.
Preclinical
studies
showed
that
conventional
adeno-associated
virus
(
AAV
)
vectors
could
correct
hyperphenylalaninemia
in
a
mouse
model
of
PKU
,
although
limitations
such
as
very
large
dose
requirement
and
relative
inefficiency
in
female
animals
were
recognized
.
An
AAV
8
-
pseudotyped
vector
was
constructed
with
a
self-complementary
AAV
(
scAAV
)
genome
for
efficient
liver
transduction
and
expression
.
Following
vector
injection
to
PKU
mice
,
blood
Phe
was
periodically
measured
by
an
enzymatic
fluorometric
assay
.
In
vivo
Phe
oxidation
was
evaluated
by
a
non-invasive
breath
test
using
[
1
-
(
13
)
C
]
Phe
.
Vector
copy
number
in
the
host
tissues
was
determined
by
quantitative
polymerase
chain
reaction
.
A
single
injection
of
1
×
10
(
11
)
-
1
×
10
(
12
)
particles
of
the
scAAV
8
vector
resulted
in
a
reduction
of
blood
Phe
to
normal
or
near-normal
levels
for
more
than
1
year
in
both
genders
.
The
treated
animals
showed
normal
level
of
in
vivo
Phe
oxidation
.
The
presence
of
>
1
copy
of
vector
DNA
per
diploid
genome
in
the
liver
was
associated
with
normal
blood
Phe
in
the
AAV-treated
PKU
mice
.
Complete
phenotypic
correction
of
PKU
mice
was
achieved
by
the
scAAV
8
vector
for
the
longest
duration
reported
to
date
.
The
vector
overcame
the
female
-
specific
disadvantage
in
AAV-mediated
liver
transduction
;
thus
,
it
offers
a
promising
platform
of
long
-lasting
gene
therapy
for
PKU
.
