Biology Reference
In-Depth Information
cat, dog, rabbit), with the exception of anti-Nogo-A treatment, where
primate experiments were conducted (
Fouad et al., 2004; Freund et al.,
2006
). Despite thorough investigations of the anti-Nogo-A treatment
over more than a decade, a contusion SCI model was never used. All other
compounds and cell-based therapies were analyzed for treatment efficacy in
rodent contusion SCI. A clear dose response curve is missing in all studies
reviewed here. Efficacy in different injury models has been reported in all
four treatments paradigms, whereas efficacy in different injury severities
has not been assessed systematically in any of the paradigms analyzed. Behav-
ioral improvement has been reported consistently—in almost all instances
investigated with the BBB locomotor rating scale. Looking specifically at
BBB locomotor assessment, the magnitude of improvement was moderate
at best, typically varying between 1 and 4 BBB score points on a scale from
0to21(
Table 7.1
). Overall, treatment timing in preclinical experiments
corresponded roughly to the time points of the drug/cell administration
in the respective clinical trials except for the anti-Nogo-A therapy. There,
specific neutralizing antibodies were exclusively delivered immediately after
the injury—in contrast to the clinical trial, where the compound was deliv-
ered within 28 days post injury. ROCK pathway inhibiting studies included
treatment delays up to 5 days, which correlated well with the clinical drug
(BA-210; Cethrin) administration (average treatment interval 52.6 h after
the injury date). Only Ngr and ROCK pathway inhibition approaches have
been replicated by independent laboratories-a criterion, which is valued
quite high in predicting robustness and efficacy of a given treatment strategy.
In case of Ngr inhibition, a follow-up study (
Steward et al., 2008
), which
represents one of the first published studies (based on the NIH funded ini-
tiative “facilities of research excellence (FORE) in SCI replication studies”)
with the intention to reassess promising therapeutic approaches in SCI by
independent investigators, failed to replicate previous restorative effects
(
Li & Strittmatter, 2003
). None of the exact compounds, which were inves-
tigated in respective clinical trials (anti-Nogo-A antibody, BA-210), were
analyzed by independent laboratories.
Beyond published requirements for preclinical experiments, additional
aspects should be considered. The key for a successful clinical translation
is to demonstrate a clear and precise structural mechanism, which explains
the observed functional improvement. For neuroprotection as underlying
mechanism, this has been accomplished by the demonstration of a significant
white/gray matter tissue sparing. For axon sprouting/regeneration as the
proposed structural mechanism, not only sprouting/regeneration for a
