Biology Reference
In-Depth Information
moderate (on average BBB locomotor score improvement between two and
four points) achieved within 4-8 weeks post injury (
Table 7.1
). Only one
study (intrathecal application of the Ngr antagonist NEP1-40) reported a
delayed treatment effect (initiation of treatment 7 days post injury) (
Li &
Strittmatter, 2003
). None of the preclinical studies in this context
investigated regenerative effects in a rodent contusion model. The treatment
with the Ngr antagonist NEP1-40 was reassessed by an independent
laboratory using the identical animal model (mouse dorsal hemisection)
and identical mode of application (
Steward et al., 2008
), which failed
to replicate previous findings of structural and functional recovery
(
Li & Strittmatter, 2003
). The antibody-mediated neutralization of
Nogo-A was not reevaluated by an independent laboratory (
Zorner &
Schwab, 2010
),
Based on the extensive preclinical investigations, an open-label multicen-
ter clinical phase I study of anti-Nogo-A treatment was initiated (
http://
this point, 51 ASIA-complete para-/tetraplegic patients received intrathecal
infusions/boli with the anti-Nogo-A antibody ATI355 within 28 days of
SCI between 2006 and 2011 (
Abel, Baron, & Casha, 2011
). No study drug
relateddeathswerereported.Inthegroupreceivingcontinuousdruginfu-
sion, five severe adverse events (infection, mechanical-device complications)
were reported. Overall, the study medication was considered to be safe.
Compared to the continuous infusion regimen, repeated intrathecal bolus in-
jections improved safety. Data regarding treatment efficacy have not been
disclosed.
Overall, the extensive preclinical evaluation of therapeutic approaches
interfering with Nogo-A/Ngr-associated axon growth inhibition demon-
strated limited structural and functional recovery without providing a clear
structural mechanism such as proper target reinnervation. The delay in treat-
ment initiation (up to 28 days) in the clinical trial was not reflected in any of
the Nogo-A related preclinical studies.
1.4. RhoA inactivation (C3 transferase, Cethrin;
see Volume 105,
Chapter 6
for more details)
The Rho-associated kinase (ROCK) signaling pathway has been identified
as an important mediator of axon growth inhibitory signaling. The analysis
of the downstream intracellular signaling cascade after myelin-associated
Ngr-p75
NTR
-complex activation identified Rho activation as the most
upstream event (
Yamashita et al., 2002
). Efforts to overcome growth