Biomedical Engineering Reference
In-Depth Information
patient's own hematopoietic stem cells followed by intravenous
reinfusion has been shown to attenuate CNS disease progression in
a clinical trial for metachromatic leukodystrophy [
28
]. Gene ther-
apy by direct intracranial injections is an attractive method for the
treatment of LSDs with CNS involvement because it provides a
permanent, onetime treatment that overcomes the BBB [
11
].
A proportion of lysosomal enzymes produced by mammalian
cells are secreted, especially when expressed at supraphysiological
levels, and can be taken up by the mannose-6-phosphate receptor
for delivery to the lysosomal compartment [
29
]. Termed “cross-
correction,” this mechanism is exploited by both ERT and gene
therapy to restore functional enzyme to diseased cells. In the case
of gene therapy, only a fraction of an organ, tissue, or cell type
need to be genetically engineered to become an endogenous fac-
tory for producing and secreting normal enzyme, which is then
available to unmodifi ed cells [
30
,
31
]. Distribution of lysosomal
enzymes from vector-transduced cells in the brain occurs by diffu-
sion in the brain parenchyma [
32
], as well as retrograde and
anterograde axonal transport to distant, interconnected structures
[
33
-
38
]. In addition, CSF fl ow in the perivascular space of
Virchow-Robin also appears to contribute to the widespread distri-
bution of lysosomal enzymes in the brain [
39
]. By utilizing the
innate properties of lysosomal enzymes and the brain itself, global
therapy throughout the CNS may be achieved from focal gene
delivery. Finally, since axonal transport is known to distribute the
Adeno Associated Virus (AAV) vector itself, remote foci of enzyme-
producing cells may be established from a single injection into stra-
tegic brain structures [
33
,
40
-
42
].
Previous studies have targeted highly interconnected struc-
tures in the CNS, such as the striatum [
43
-
45
], deep cerebellar
nuclei (DCN) [
46
], ventral tegmental area (VTA) [
40
], or thala-
mus [
47
], relying heavily on axonal transport of enzymes and pos-
sibly also on interstitial fl uid fl ow [
33
,
40
-
42
,
48
]. An alternative
approach is to target ependymal cells in the ventricular system
allowing secretion of enzyme into CSF for subsequent distribution
[
39
,
49
]. Our work has focused on targeting AAV vectors to the
thalamus for the widespread distribution of lysosomal enzymes in
the mammalian brain. The thalamus receives afferent input from
many structures throughout the CNS and relays the information
to the cerebral cortex, from which it also receives reciprocal input.
Therefore, the thalamus can be viewed as the central node of a
“built-in” network for the dissemination of lysosomal enzymes
throughout the CNS via axonal transport. Though AAV gene
delivery to the thalamus can supply therapeutic levels of a lyso-
somal enzyme to the cerebrum, it is not suffi cient to treat the cer-
ebellum and spinal cord [
47
,
50
]. Therefore, we enhanced
therapeutic effi cacy by combining bilateral thalamic infusion with
bilateral injections of the DCN or delivery into CSF via the cerebral
lateral ventricles.
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