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Pretransplant mobilization with granulocyte colony-stimulating factor improves B-cell reconstitution by lentiviral vector gene therapy in SCID-X1 mice.
[severe combined immunodeficiency]
Hematopoietic
stem
cell
(
HSC
)
gene
therapy
is
a
demonstrated
effective
treatment
for
X-
linked
severe
combined
immunodeficiency
(
SCID
-X
1
)
,
but
B-
cell
reconstitution
and
function
has
been
deficient
in
many
of
the
gene
therapy
treated
patients
.
Cytoreductive
preconditioning
is
known
to
improve
HSC
engraftment
,
but
in
general
it
is
not
considered
for
SCID
-X
1
since
the
poor
health
of
most
of
these
patients
at
diagnosis
and
the
risk
of
toxicity
preclude
the
conditioning
used
in
standard
bone
marrow
stem
cell
transplantation
.
We
hypothesized
that
mobilization
of
HSC
by
granulocyte
colony-stimulating
factor
(
G-CSF
)
should
create
temporary
space
in
bone
marrow
niches
to
improve
engraftment
and
thereby
B-
cell
reconstitution
.
In
the
present
pilot
study
supplementing
our
earlier
preclinical
evaluation
(
Huston
et
al
.
,
2011
)
,
Il
2
rg
(
-
/
-
)
mice
pretreated
with
G-CSF
were
transplanted
with
wild-
type
lineage
negative
(
Lin
(
-
)
)
cells
or
Il
2
rg
(
-
/
-
)
Lin
(
-
)
cells
transduced
with
therapeutic
IL
2
RG
lentiviral
vectors
.
Mice
were
monitored
for
reconstitution
of
lymphocyte
populations
,
level
of
donor
cell
chimerism
,
and
antibody
responses
as
compared
to
2
 
Gy
total
body
irradiation
(
TBI
)
,
previously
found
effective
in
promoting
B-
cell
reconstitution
.
The
results
demonstrate
that
G-CSF
promotes
B-
cell
reconstitution
similar
to
low
-dose
TBI
and
provides
proof
of
principle
for
an
alternative
approach
to
improve
efficacy
of
gene
therapy
in
SCID
patients
without
adverse
effects
associated
with
cytoreductive
conditioning
.
