Biomedical Engineering Reference
In-Depth Information
Interestingly, the developmental stage at which the virus should be
introduced to achieve the maximal effect is of great importance.
Systemic delivery of scAAV9-SMN into SMN
Time Point of Application
7 model at later time
points signifi cantly decreases the therapeutic benefi ts of the vector.
Foust et al. [
3
] reported that systemic injection of scAAV9-SMN at
postnatal day 2 (P2) leads to ~250 days of survival as P1 injection.
However, P5 injection led to ~15 days increase in survival and P10
injection had no benefi cial effect. The authors concluded that trans-
duction is altered in the CNS depending on the time of injection.
P2 injection resulted in high level of transduction in motor neurons,
while P10 injection led mostly to glial transduction [
3
]. Whether
this pattern of transduction is responsible for the lack of rescue in
P10-injected mice remains to be elucidated. In another study, sys-
temic injection of the scAAV9-GFP (through tail vein) resulted in
motor neuron transduction up to 28 % in adult mice and 15 % in
adult cats [
63
]. Since the promoters driving the GFP transgene
expression were different in these two studies [chicken
ʔ
-actin
hybrid (CBA) vs. cytomegalovirus (CMV), respectively], the possi-
bility of the promoters functioning differently in neuronal system of
adult mice should be considered. An additional question is whether
a similar pattern of transduction occurs following ICV injection at
delayed time points. Nevertheless, as the likelihood of scAAV9-
SMN entering the clinic increases rapidly, determining the underly-
ing mechanism that prevents rescue at delayed time points is essential
for patients who will miss the critical time course of therapy.
ʲ
In two additional studies, the impact of scAAV9-SMN through
temporal facial vein injection was investigated in newborn SMA
mice. In the fi rst study, the systemic injection of 1 × 10
11
genomic
copies of cAAV9 expressing a codon-optimized h
SMN
cDNA
resulted in signifi cant improvements in motor function and an
increase in median survival up to 69 days in 80 % of treated animals
[
22
]. This survival rate is signifi cantly less than that reported by
Foust et al. [
3
]. Since in both studies the injections were adminis-
tered at P1-2, it is hypothesized that the greater increase in sur-
vival of the mice reported by Foust et al. is due to a fi vefold higher
dose of the virus [
22
]. This speculation may not be justifi ed since
the SMN expression in these viruses was driven by two different
promoters. Moreover, a second study indicated that systemic injec-
tion of 4.5 × 10
10
genomic copies of scAAV9-hSMN (also codon-
optimized) into newborn SMA mice resulted in survival rate of
more than 200 days in 50 % of the treated mice [
21
]. In this study,
46 % of the injected mice died by 65 days. These fi ndings contra-
dict the possibility that the dose effect is totally responsible for the
survival rate and suggest that additional factors in the viral vector
play a role in the effi cacy of the virus. These factors may include the
type of the promoter driving the SMN expression, the method of
Viral Titer
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