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A next step in adeno-associated virus-mediated gene therapy for neurological diseases: regulation and targeting.
[canavan disease]
Recombinant
adeno-associated
virus
(
rAAV
)
vectors
mediating
long
term
transgene
expression
are
excellent
gene
therapy
tools
for
chronic
neurological
diseases
.
While
rAAV
2
was
the
first
serotype
tested
in
the
clinics
,
more
efficient
vectors
derived
from
the
rh
10
serotype
are
currently
being
evaluated
and
other
serotypes
are
likely
to
be
tested
in
the
near
future
.
In
addition
,
aside
from
the
currently
used
stereotaxy-guided
intraparenchymal
delivery
,
new
techniques
for
global
brain
transduction
(
by
intravenous
or
intra-cerebrospinal
injections
)
are
very
promising
.
Various
strategies
for
therapeutic
gene
delivery
to
the
central
nervous
system
have
been
explored
in
human
clinical
trials
in
the
past
decade
.
Canavan
disease
,
a
genetic
disease
caused
by
an
enzymatic
deficiency
,
was
the
first
to
be
approved
.
Three
gene
transfer
paradigms
for
Parkinson
's
disease
have
been
explored
:
converting
L-
dopa
into
dopamine
through
AADC
gene
delivery
in
the
putamen
;
synthesizing
GABA
through
GAD
gene
delivery
in
the
overactive
subthalamic
nucleus
and
providing
neurotrophic
support
through
neurturin
gene
delivery
in
the
nigro-striatal
pathway
.
These
pioneer
clinical
trials
demonstrated
the
safety
and
tolerability
of
rAAV
delivery
in
the
human
brain
at
moderate
doses
.
Therapeutic
effects
however
,
were
modest
,
emphasizing
the
need
for
higher
doses
of
the
therapeutic
transgene
product
which
could
be
achieved
using
more
efficient
vectors
or
expression
cassettes
.
This
will
require
re
-addressing
pharmacological
aspects
,
with
attention
to
which
cases
require
either
localized
and
cell-
type
specific
expression
or
efficient
brain
-
wide
transgene
expression
,
and
when
it
is
necessary
to
modulate
or
terminate
the
administration
of
transgene
product
.
The
ongoing
development
of
targeted
and
regulated
rAAV
vectors
is
described
.