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A combined therapeutic approach for pyruvate dehydrogenase deficiency using self-complementary adeno-associated virus serotype-specific vectors and dichloroacetate.
[pyruvate dehydrogenase deficiency]
We
determined
the
ability
of
self-complementary
adeno-associated
virus
(
scAAV
)
vectors
to
deliver
and
express
the
pyruvate
dehydrogenase
E
1
alpha
subunit
gene
(
PDHA
1
)
in
primary
cultures
of
skin
fibroblasts
from
3
patients
with
defined
mutations
in
PHDA
1
and
3
healthy
subjects
.
Cells
were
transduced
with
scAAV
vectors
containing
the
cytomegalovirus
promoter-driven
enhanced
green
fluorescent
protein
(
EGFP
)
reporter
gene
at
a
vector
:
cell
ratio
of
200
.
Transgene
expression
was
measured
72
h
later
.
The
transduction
efficiency
of
scAAV
2
and
scAAV
6
vectors
was
3
-
to
5
-
fold
higher
than
that
of
the
other
serotypes
,
which
were
subsequently
used
to
transduce
fibroblasts
with
wild-
type
PDHA
1
cDNA
under
the
control
of
the
chicken
beta
-action
(
CBA
)
promoter
at
a
vector
:
cell
ratio
of
1000
.
Total
PDH
-
specific
activity
and
E
1
alpha
protein
expression
were
determined
10
days
post-transduction
.
Both
vectors
increased
E
1
alpha
expression
40
-
60
%
in
both
control
and
patient
cells
,
and
increased
PDH
activity
in
two
patient
cell
lines
.
We
also
used
dichloroacetate
(
DCA
)
to
maximally
activate
PDH
through
dephosphorylation
of
E
1
alpha
.
Exposure
for
24
h
to
5
mM
DCA
increased
PDH
activity
in
non-transduced
control
(
mean
37
%
increase
)
and
PDH
deficient
(
mean
44
%
increase
)
cells
.
Exposure
of
transduced
patient
fibroblasts
to
DCA
increased
PDH
activity
up
to
90
%
of
the
activity
measured
in
untreated
control
cells
.
DCA
also
increased
expression
of
E
1
alpha
protein
and
,
to
variable
extents
,
that
of
other
components
of
the
PDH
complex
in
both
non-transduced
and
transduced
cells
.
These
data
suggest
that
a
combined
gene
delivery
and
pharmacological
approach
may
hold
promise
for
the
treatment
of
PDH
deficiency
.
Diseases
Validation
Diseases presenting
"e1alpha protein expression were determined 10 days post-transduction"
symptom
pyruvate dehydrogenase deficiency
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