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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://
clinicaltrials.gov/ct2/show/NCT00406016?term ¼ ATI355&rank ¼ 1 ). At
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
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