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Somatic correction of junctional epidermolysis bullosa by a highly recombinogenic AAV variant.
[junctional epidermolysis bullosa]
Definitive
correction
of
disease
causing
mutations
in
somatic
cells
by
homologous
recombination
(
HR
)
is
an
attractive
therapeutic
approach
for
the
treatment
of
genetic
diseases
.
However
,
HR
-based
somatic
gene
therapy
is
limited
by
the
low
efficiency
of
gene
targeting
in
mammalian
cells
and
replicative
senescence
of
primary
cells
ex
vivo
,
forcing
investigators
to
explore
alternative
strategies
such
as
retro-
and
lentiviral
gene
transfer
,
or
genome
editing
in
induced
pluripotent
stem
cells
.
Here
,
we
report
correction
of
mutations
at
the
LAMA
3
locus
in
primary
keratinocytes
derived
from
a
patient
affected
by
recessive
inherited
Herlitz
junctional
epidermolysis
bullosa
(
H-
JEB
)
disorder
using
recombinant
adenoassociated
virus
(
rAAV
)
-
mediated
HR
.
We
identified
a
highly
recombinogenic
AAV
serotype
,
AAV-DJ
,
that
mediates
efficient
gene
targeting
in
keratinocytes
at
clinically
relevant
frequencies
with
a
low
rate
of
random
integration
.
Targeted
H-
JEB
patient
cells
were
selected
based
on
restoration
of
adhesion
phenotype
,
which
eliminated
the
need
for
foreign
sequences
in
repaired
cells
,
enhancing
the
clinical
use
and
safety
profile
of
our
approach
.
Corrected
pools
of
primary
cells
assembled
functional
laminin-
332
heterotrimer
and
fully
reversed
the
blistering
phenotype
both
in
vitro
and
in
skin
grafts
.
The
efficient
targeting
of
the
LAMA
3
locus
by
AAV-DJ
using
phenotypic
selection
,
together
with
the
observed
low
frequency
of
off-target
events
,
makes
AAV-DJ
based
somatic
cell
targeting
a
promising
strategy
for
ex
vivo
therapy
for
this
severe
and
often
lethal
epithelial
disorder
.
Diseases
Validation
Diseases presenting
"primary cells"
symptom
gm1 gangliosidosis
junctional epidermolysis bullosa
primary effusion lymphoma
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