Biology Reference
In-Depth Information
1.3. Anti-Nogo-A
Almost 25 years ago, membrane proteins of CNS myelin (NI-250) were
identified to inhibit axon growth
in vitro
(
Schwab & Caroni, 1988
). In
the following years, specific antibodies developed to neutralize respective
myelin-associated molecules (IN-1 antibody) promoted axon regrowth in
small animal models after corticospinal tract (CST) lesions at brainstem
and spinal cord level (
Bregman et al., 1995; Caroni & Schwab, 1988;
Schnell & Schwab, 1990; Thallmair, Metz, Z'Graggen, et al., 1998
).
After purifying and cloning of the main component of NI-250, Nogo-A
(
Chen, Huber, van der Haar, et al., 2000; Grandpre, Nakamura,
Vartanian, et al., 2000
), new antibodies (11C7 and 7B12) were generated.
Further, studies identified the inhibition mediating receptor of soluble
Nogo-66 (Ngr) (
Fournier et al., 2001
). Albeit not mediating the inhibitory
effects of membrane-bound amino Nogo, this receptor was identified to
mediate inhibitory effects of two other myelin-associated proteins (Mag,
Omgp) (
Domeniconi, Cao, Spencer, et al., 2002; Liu, Fournier, Grandpre,
et al., 2002; Wang, Koprivica, Kim, et al., 2002
). Consequently, it was
hypothesized that there is redundancy of inhibitory molecules converging
to the same receptor complex (Ngr-p75
NTR
)(
Filbin, 2003; Wang, Kim,
Sivasankaran, et al., 2002; Wong, Henley, Kanning, et al., 2002;
Yamashita, Higuchi, & Tohyama, 2002
). In line with this redundancy,
several rodent gene knockout strategies exhibited heterogeneous (and even
strain dependent) results with respect to axonal growth inhibition (
Cafferty,
Kim, Lee, et al., 2007; Dimou, Schnell, Montani, et al., 2006; Kim, Li,
Grandpre, et al., 2003; Kim, Liu, Park, et al., 2004; Simonen, Pedersen,
Weinmann, et al., 2003; Zheng, Atwal, Ho, et al., 2005; Zheng, Ho, Li,
et al., 2003
).
Numerous related preclinical studies investigated the effects of inhibiting
Nogo-A- or Ngr-mediated signaling with specific antibodies or peptide
administration (intracerebral/intrathecal/intraperitoneal/subcutaneous) to
elicit structural and functional recovery after SCI (
Bregman et al., 1995;
Fouad et al., 2004; Freund et al., 2006; Grandpre et al., 2002; Li et al.,
2004; Li & Strittmatter, 2003; Liebscher et al., 2005; Merkler et al.,
2001; Schnell & Schwab, 1990
). In terms of structural repair, sprouting
of CST axons at supraspinal and spinal level (above and below the
lesion) was the most frequent correlate. A confirmation of target neuron
reinnervation by sprouting axons has not been reported. The most
frequent reported functional outcome parameter was BBB locomotor
assessment. Across the board,
locomotor improvement effect size was
