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Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome.
[omenn syndrome]
Recombination-activating
gene
1
(
RAG
1
)
deficiency
results
in
severe
combined
immunodeficiency
(
SCID
)
caused
by
a
complete
lack
of
T
and
B
lymphocytes
.
If
untreated
,
patients
succumb
to
recurrent
infections
.
We
sought
to
develop
lentiviral
gene
therapy
for
RAG
1
-
induced
SCID
and
to
test
its
safety
.
Constructs
containing
the
viral
spleen-focus-forming
virus
(
SF
)
,
ubiquitous
promoters
,
or
cell
type
-
restricted
promoters
driving
sequence-optimized
RAG
1
were
compared
for
efficacy
and
safety
in
sublethally
preconditioned
Rag
1
(
-
/
-
)
mice
undergoing
transplantation
with
transduced
bone
marrow
progenitors
.
Peripheral
blood
CD
3
(
+
)
T
-
cell
reconstitution
was
achieved
with
SF
,
ubiquitous
promoters
,
and
cell
type
-
restricted
promoters
but
3
-
to
18
-
fold
lower
than
that
seen
in
wild-
type
mice
,
and
with
a
compromised
CD
4
(
+
)
/
CD
8
(
+
)
ratio
.
Mitogen-mediated
T
-
cell
responses
and
T
cell-dependent
and
T
cell-independent
B-
cell
responses
were
not
restored
,
and
T
-
cell
receptor
patterns
were
skewed
.
Reconstitution
of
mature
peripheral
blood
B
cells
was
approximately
20
-
fold
less
for
the
SF
vector
than
in
wild-
type
mice
and
often
not
detectable
with
the
other
promoters
,
and
plasma
immunoglobulin
levels
were
abnormal
.
Two
months
after
transplantation
,
gene
therapy-treated
mice
had
rashes
with
cellular
tissue
infiltrates
,
activated
peripheral
blood
CD
44
(
+
)
CD
69
(
+
)
T
cells
,
high
plasma
IgE
levels
,
antibodies
against
double
-stranded
DNA
,
and
increased
B
cell-activating
factor
levels
.
Only
rather
high
SF
vector
copy
numbers
could
boost
T
-
and
B-
cell
reconstitution
,
but
mRNA
expression
levels
during
T
-
and
B-
cell
progenitor
stages
consistently
remained
less
than
wild-
type
levels
.
These
results
underline
that
further
development
is
required
for
improved
expression
to
successfully
treat
patients
with
RAG
1
-
induced
SCID
while
maintaining
low
vector
copy
numbers
and
minimizing
potential
risks
,
including
autoimmune
reactions
resembling
Omenn
syndrome
.
Diseases
Validation
Diseases presenting
"high plasma"
symptom
classical phenylketonuria
omenn syndrome
scrub typhus
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