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Efficient KRT14 targeting and functional characterization of transplanted human keratinocytes for the treatment of epidermolysis bullosa simplex.
[epidermolysis bullosa simplex]
Inherited
skin
blistering
conditions
collectively
named
epidermolysis
bullosa
(
EB
)
cause
significant
morbidity
and
mortality
due
to
the
compromise
of
the
skin
's
barrier
function
,
the
pain
of
blisters
,
inflammation
,
and
in
some
cases
scaring
and
cancer
.
The
simplex
form
of
EB
is
usually
caused
by
dominantly
inherited
mutations
in
KRT
5
or
KRT
14
.
These
mutations
result
in
the
production
of
proteins
with
dominant-negative
activity
that
disrupt
polymerization
of
intermediate
filaments
in
the
basal
keratinocyte
layer
and
result
in
a
weak
epidermal-dermal
junction
.
The
genome
of
adeno-associated
virus
(
AAV
)
vectors
can
recombine
with
chromosomal
sequence
so
that
mutations
can
be
corrected
,
or
production
of
proteins
with
dominant-negative
activity
can
be
disrupted
.
We
demonstrate
a
clinically
feasible
strategy
for
efficient
targeting
of
the
KRT
14
gene
in
normal
and
EB-affected
human
keratinocytes
.
Using
a
gene
-targeting
vector
with
promoter
trap
design
,
targeted
alteration
of
one
allele
of
KRT
14
occurred
in
100
%
of
transduced
cells
and
transduction
frequencies
ranged
from
0
.
1
to
0
.
6
%
of
total
cells
.
EBS
patient
keratinocytes
with
precise
modifications
of
the
mutant
allele
are
preferentially
recovered
from
targeted
cell
populations
.
Single
epidermal
stem
cell
clones
produced
histologically
normal
skin
grafts
after
transplantation
to
athymic
mice
and
could
generate
a
sufficient
number
of
cells
to
transplant
the
entire
skin
surface
of
an
individual
.
