Biomedical Engineering Reference
In-Depth Information
Based on the recent fi ndings of the heart defects in SMA mouse
models [
64
-
66
], it was suggested that intravenous (IV) injection
leads to better survival which is possibly due to its direct cardiac
transduction that protects the heart [
67
]. However, direct com-
parison of the two injection methods requires all parameters to be
identical, and in this case, the AAV serotypes were different. Even
though the superiority of AAV9 to AAV8 in global cardiac gene
transfer is reported [
68
,
69
] and cardiac malfunction could very
well be one of the many possible reasons for premature death of
scAAV8-SMN-injected mice, a direct proof that the IV injection is
more advantageous than ICV injection was lacking at the time of
this publication. Direct comparison of IV and ICV injections in
SMA gene therapy was performed in our lab which will be dis-
cussed in the following section.
The clinical potential of scAAV9 in neurodegenerative diseases
was verifi ed by the ability of scAAV9 to pass the blood-brain barrier
and transduce motor neurons when injected into the nonhuman
primates [
3
,
62
,
63
,
70
,
71
]. The most extensive study was per-
formed by Bevan et al. in which the CNS accessibility was tested in
cynomolgus macaques by IV injection of scAAV9-GFP at various
ages up to 3 years of age [
72
]. They observed transduction of motor
neurons in the spinal cord as well as extensive transduction of glial
cells in the brain at all the time points tested. Systemic delivery also
resulted in the transduction of skeletal muscles along with periph-
eral organs. They also examined the transgene expression by the
directed targeting of the CNS using intrathecal and intracisternal
injection of scAAV9-GFP into newborn pigs. This type of delivery
may be benefi cial for less severe cases which merely require CNS
transduction and also reduces the amount of viral vectors required.
Both delivery routes using either the cisternal space at the base of
the skull or the intrathecal space at L5 led to GFP expression only
in the CNS including the dorsal root ganglia, the gray and white
matter of the spinal cord including motor neurons at all levels of the
spinal cord. This study concluded that the consistency of scAAV9 in
transduction of the CNS in a broad spectrum of species and the
choice of different delivery routes makes it a suitable vector for neu-
rodegenerative pediatric diseases applied at various ages [
72
].
Some evidence suggests that the rescue of peripheral organs in
addition to motor neurons, especially in severe cases of disease, is
necessary for the complete rescue of the SMA phenotype [
39
,
46
,
73
,
74
]. Therefore, the transduction of the peripheral organs
which is a defi nite consequence of the systemic injection plays a
benefi cial role in SMA gene therapy. Our group aimed to shed
light on the suitability of different delivery methods in SMA gene
therapy. We examined two injection methods (IV and ICV) directly
by utilizing an identical viral vector preparation and titer (2 × 10
10
genomic particles), which was approximately ten times less than
Delivery Routes
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