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Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa.
[junctional epidermolysis bullosa]
Mutations
of
the
LAMB
3
gene
cause
a
lethal
form
of
junctional
epidermolysis
bullosa
(
JEB
)
.
We
hypothesized
that
early
intra-
amniotic
gene
transfer
in
a
severe
murine
model
of
JEB
would
improve
or
correct
the
skin
phenotype
.
Time-dated
fetuses
from
heterozygous
LAMB
3
(
IAP
)
breeding
pairs
underwent
ultrasound
guided
intra-
amniotic
injection
of
lentiviral
vector
encoding
the
murine
LAMB
3
gene
at
embryonic
day
8
(
E
8
)
.
Gene
expression
was
monitored
by
immunohistochemistry
.
The
transgenic
laminin-β
3
chain
was
shown
to
assemble
with
its
endogenous
partner
chains
,
resulting
in
detectable
amounts
of
laminin-
332
in
the
basement
membrane
zone
of
skin
and
mucosa
.
Ultrastructually
,
the
restoration
of
∼
60
%
of
hemidesmosomal
structures
was
also
noted
.
Although
we
could
correct
the
skin
phenotype
in
11
.
9
%
of
homozygous
LAMB
3
(
IAP
)
mice
,
none
survived
beyond
48
 
h
.
However
,
skin
transplants
from
treated
E
18
homozygous
LAMB
3
(
IAP
)
fetuses
maintained
normal
appearance
for
6
months
with
persistence
of
normal
assembly
of
laminin-
332
.
These
results
demonstrate
for
the
first
time
long
-term
phenotypic
correction
of
the
skin
pathology
in
a
severe
model
of
JEB
by
in
vivo
prenatal
gene
transfer
.
Although
survival
remained
limited
due
to
the
limitations
of
this
mouse
model
,
this
study
supports
the
potential
for
treatment
of
JEB
by
prenatal
gene
transfer
.
