Table 3.

Anti-Nogo Approaches

Study	Animal model and injury model	Intervention and timing	Experimental group	Outcome: histologic/biochemical/physiological/behavioral
Maier et al., 2009	Model: adult female SD rats, 200−250 g Injury: T8 T-shaped lesion (bilateral dorsal hemisection and complete midline transection)	Anti(amino)Nogo-A Ab (11C7) • Intrathecal infusion at T10 started at 0 h PI, then × 14 d (Ab solution 3 mg/mL) minipump delivered 5 μL/h, 3.1 μg IgG/mL Treadmill training (bipedal & quadrupedal)	SCI + • 11C7, non-trained • 11C7, trained • Control IgG, non-trained • Control IgG, trained N = 17/group for behavior and n = 7/group for morphology	Histologic/biochemical/physiological: 11C7 treatment increased the number of CST fibers with a significant increase after training and led to significant serotonergic innervation of motoneurons. • No difference in nociceptive primary afferent fibers (CGRP+) Behavioral: at 9 wk PI, 11C7-treated rats displayed consistent step cycles with good coordination and a very low level of paw drag, approaching the values of intact rats. • 11C7 treatment significantly improved performance in inclined grid walk. • Training alone improved locomotor function. • After combined treatment (11C7 + training), animals displayed worse locomotor function than 11C7 alone, suggesting interference of both movement strategies.
Freund et al., 2009	Model: male or female macaque monkeys, 3–5 kg, 3.5−6.9 yr old Injury: C7-C8 unilateral transection	Anti(amino)Nogo-A Ab (11C7 or MAb hNogo-A) • Ab concentrations of 3.7−10 mg/mL in PBS; delivered intrathecally 3−5 mm rostral to the lesion via osmotic minipump × 4 wk (started at 0 h PI)	SCI + • Anti-Nogo-A (n = 7; 3 hNogo-A, 4 11C7) • Control antibodies (n = 6)	Histologic/biochemical/physiological: This re-examines Freund results from 2006. Statistical analysis was conducted for recovery as a function of the size of the lesion. • The normalized number of axonal swellings caudal to the lesion and normalized number of CS axons crossing midline at C5 as a function of the lesion extent are significantly different in the groups. Behavioral: With modified Brinkman board test, anti-Nogo-A antibody-treated monkeys demonstrated significantly better recovery of their manual dexterity than the control antibody-treated monkeys in the total number of pellets and the contact time. • Animals receiving anti-Nogo-A antibody 1 wk PI exhibited complete recovery of function.
Wannier-Morino et al., 2008	Model: male or female macaque monkeys, 3–5 kg, 3.5−6.9 yr old Injury: C7-C8 unilateral transection	Anti(amino)Nogo-A Ab (11C7 or MAb hNogo-A) • Ab concentrations of 3.7−10 mg/mL in PBS; delivered intrathecally 3−5 mm rostral to the lesion via osmotic minipump × 4 wk (started at 0 h PI)	SCI + • Anti-Nogo-A (n = 7; 4hNogo-A, 3 11C7) • Control antibodies (n = 4) Uninjured controls (n = 4)	Histologic/biochemical/physiological: Anti-Nogo-A antibody treatment at the site of the lesion did not prevent reduction of the number of rubrospinal neurons in the contralesional red nucleus nor did it prevent shrinkage. Behavioral: not reported
Beaud et al., 2008	Model: adult macaque monkeys Injury: variable lesions at C7-8 targeting a hemisection	Anti(amino)Nogo-A Ab (11C7 or MAb hNogo-A) • Ab concentrations of 3.7−10 mg/mL in PBS; delivered intrathecally 3−5 mm rostral to the lesion via osmotic minipump × 4 wk (started at 0 h PI)	SCI + • Anti Nogo-A (n = 5; 4 hNogo-A and 1 11C7) • Control IgG (n = 4) Uninjured controls (n = 5)	Histologic/biochemical/physiological: no effect on atrophy of lesioned cell bodies Behavioral: not reported
Steward et al., 2008	Model: adult female C57Bl/6 mice Injury: T8 dorsal hemisection	NEP1-40 (Nogo 66) subcutaneous injection • Given at 0 and 4 h PI, or given at 7 d PI (delayed)	SCI + • NEP1-40 • Reverse peptide • Control N = 10−11/group for each	Histologic/biochemical/physiological: modest effect on axonal sprouting/regeneration Behavioral: no locomotor improvement (Note: This is an NIH-funded replication study of Li and Strittmatter, 2003 [see below].)
Cao et al., 2008	Model: adult female SD rats Injury: C4 right lateral funiculus section	NEP1-40 (Nogo 66) • 500 mM NEP1-40 via intrathecal infusion at 0.3 mL/h for 28 d • Started at 0 h PI	SCI + • NEP1-40 (n = 8) • Control (n = 7)	Histologic/biochemical/physiological: Rubrospinal tract and 5-HT sprouting increased. Behavioral: Gait and forelimb use recovered (but not to the end of experiment).
Atalay et al., 2007	Model: adult male SD rats Injury: T10 hemisection	NEP1-40 (Nogo 66) • Given at 0 h PI, directly applied to injury site	SCI + • NEP1-40 (n = 23) • Control (n = 21)	Histologic/biochemical/physiological: improved preservation of injured axons, enhanced axonal sprouting Behavioral: significantly enhanced motor recovery at 8 and 21 d PI
Freund et al., 2007	Model: adult macaque monkeys Injury: variable lesions at C7-8 targeting a hemisection	Anti(amino)Nogo A Ab (11C7 or MAb hNogo A) • Ab concentrations of 3−10 mg/mL in PBS; delivered intrathecally 3–5 mm rostral to the lesion via osmotic minipump × 4 wk (started at 0 h PI)	SCI + • Anti Nogo (11C7, n = 7) • Anti Nogo (hNogo-A, n = 6) Uninjured controls (n = 3)	Histologic/biochemical/physiological: fewer retraction bulbs, increased axon arbor length, increased CST sprouting rostral to injury site Behavioral: not assessed (some animals were assessed in Freund et al., 2006)
Freund et al., 2006	Model: adult macaque monkeys, 2.5−5.5 kg, 3−4 yr old Injury: variable lesions at C7-8 targeting a hemisection	Anti(amino)Nogo A Ab (11C7 or MAb hNogo A) • Ab concentrations of 3−10 mg/mL in PBS; delivered intrathecally 3–5 mm rostral to the lesion via osmotic minipump × 4 wk (started at 0 h PI)	SCI + • Anti Nogo (11C7, n = 4) • Anti Nogo (hNogo-A, n = 2) • Control IgG (n = 6)	Histologic/biochemical/physiological: enhanced CST sprouting distal to injury site (SCI lesion variable) Behavioral: improvement in reaching performance
Wang et al., 2006	Model: adult female SD rats Injury: Moderate T8 contusion	NgR(310)ecto-Fc, intrathecally • Via minipump at 0.29 mg/kg/day × 28 d; started at time of injury or 3 d PI	SCI + • NgR(310) ecto-Fc (n = 8) • Control (n = 8)	Histologic/biochemical/physiological: increased 5-HT fiber sprouting Behavioral: enhanced locomotor recovery (BBB) in both acute and delayed group. Delayed therapy was as efficacious as acute therapy.
Liebscher et al., 2005	Model: female Lewis rats, 160−190 g Injury: T8 T-shaped lesion (bilateral dorsal hemisection and complete midline transection)	Anti (amino) Nogo-A Ab (11C7 or 7B12) • Intrathecal infusion at T10 started at 0 h PI, then × 14 d (Ab solution 3 mg/mL) minipump delivered 5 mL/h, 3.1 mg IgG/mL	SCI + • Anti Nogo A Ab (7B12) • Anti Nogo A Ab (11C7) • Control Ab Total n = 69; n/group not reported	Histologic/biochemical/physiological: Anti–Nogo-A: CST sprouting was significantly higher in both treated groups than in control. Enhanced CST regeneration Behavioral: improvement on horizontal ladder, swimming, but not in BBB score
Fouad et al., 2004	Model: monkey Callitrix jacchus (marmoset) Injury: T8 dorsolateral quadrant	MAb IN-1 • Ab-secreting hybridoma implanted into CSF at 0 h PI	SCI + • IN-1 (n = 4) • Control Ab (n = 2)	Histologic/biochemical/physiological: growth and regeneration of CST up to 5 mm caudal of lesion Behavioral: not reported
Li et al., 2004	Model: adult female SD rats Injury: T6/7, dorsal hemisection	NgR(310) ecto-Fc, intrathecal • Given at 0 h PI	SCI + • NgR(310) ecto-Fc (n = 6) • Control (n = 6)	Histologic/biochemical/physiological: Intrathecal NgR(310) ecto-Fc ecto stimulates dCST sprouting in rats rostral to an over-hemisection, induces sprouting and synaptic connection of CST fibers and serotonergic axons, and improves electrophysiology measures (motor-evoked potentials). Behavioral: improved locomotor recovery
Li and Strittmatter, 2003	Model: adult Bl/6 mice Injury: T6 dorsal over-hemisection	NEP1-40 (Nogo 66) • Given at 0 and 4 h PI or given at 7 d PI (delayed) Subcutaneous infusion with minipump × 14 d, or daily intraperitoneal injections × 14 d	• NEP1-40 (n = 57) • Control (n = 34)	Histologic/biochemical/physiological: extensive growth of 5-HT and CST fibers Behavioral: positive effect of delayed treatment on locomotor recovery, dose-dependent effects following systemic application
GrandPré et al., 2002	Model: female SD rats, 175−250 g Injury: T6/7, dorsal hemisection	NEP1-40 (Nogo 66) • 75 μg/kg, given intrathecally at 0 h PI and then for 4 wk	SCI + • NEP1-40 (n = 16) • Control (n = 18)	Histologic/biochemical/physiological: CST sprouting rostral to lesion. NEP1-40 treatment prevented decrease in the density of 5-HT-positive fibers below injury site. Behavioral: substantially improved recovery in open field locomotion measured in a subgroup of animals (n = 6 and 7)
Raineteau et al., 2002	Model: adult Lewis rats Injury: bilateral pyramidotomy	MAb IN-1 • Ab-secreting hybridoma implanted at 0 h PI	SCI + • IN-1 (n = 31) • Control Ab (n = 24) • No treatment (n = 11) No SCI (n = 25)	Histologic/biochemical/physiological: reorganization of rubrospinal tract. Numerous RST fibers entered the ventral horn after bPT and IN-1 Ab treatment, targeted specially to the ventral regions of the spinal grey matter. RST fibers invading the ventral horn made close appositions with motoneurons. • Electrophysiology: Reduced latency and threshold for muscle stimulation in IN-1 Ab treated animals confirmed the innervation of the proximal motoneuron pool. Behavioral: not reported
Merkler et al., 2001	Model: Lewis Rats, 200–250 g Injury: T8, large over-hemisection (2/3 of cord)	MAb IN-1 • Ab-secreting hybridoma implanted at 0 h PI	SCI + • IN-1 • Control Ab N = 10/group	Histologic/biochemical/physiological: not reported Behavioral: recovery in locomotion (electromyographic recordings, kinematics, and horizontal ladder)
Raineteau et al., 2001	Model: Lewis rats, 2.5 mo Injury: bilateral pyramidotomy	MAb IN-1 • Ab-secreting hybridoma implanted at 0 h PI	SCI + • IN-1 (n = 23) • Control Ab (n = 19) • Lesion only (n = 7) No SCI (n = 12)	Histologic/biochemical/physiological: 2-fold increase in the number of collaterals emerging from rubrospinal tract and brain stimulation Behavioral: recovery in grasping
Brosamle et al., 2000	Model: female Lewis rats, 6−8 wk old Injury: T8 bilateral dorsal hemisection	IN-1 Fab • 5 mg/mL for 0.5 μL/h × 14 d delivery via minipump, started at 0 h PI	SCI + • IN-1 Fab (n = 18) • Neutralized Fab (n = 7) • BSA (control, n = 5)	Histologic/biochemical/physiological: rIN-1 Fab. Regenerating fibers grew >9 mm beyond the lesion. Behavioral: not reported
Raineteau et al., 1999	Model: adult Lewis rats, 2.5 mo old Injury: unilateral pyramidotomy	MAb IN-1 • Ab-secreting hybridoma implanted at 0 h PI	SCI + • IN-1 (n = 6) • Control (n = 6) • Lesion only (n = 6)	Histologic/biochemical/physiological: regenerative sprouting enhanced Behavioral: reported in Z'Graggen et al., 1998
Thallmair et al., 1998	Model: Lewis rats, 2−3 mo old Injury: unilateral pyramidotomy	MAb IN-1 • Ab-secreting hybridoma implanted at 0 h PI	SCI + • IN-1 • Control Ab N = 25/group	Histologic/biochemical/physiological: increase in sprouting, crossing the midline, branching, bouton-like structures, increased number of cortico-bulbar projections from parvocellular red nucleus and pons Behavioral: enhanced recovery in grasping, rope climbing, and sticky paper test
Von Meyenburg et al., 1998	Model: Lewis rats, 90−120 g, 5−6 wk old Injury: T8 bilateral dorsal hemisection	MAb IN-1 • Hybridoma implanted at 2 or 8 wk PI (with NT-3)	SCI + • IN-1 + NT-3 (n = 9, 2 wk) • Control Ab + NT-3 (n = 8, 2 wk) • IN-1 + NT-3 (n = 20, 8 wk) • Control Ab + NT-3 (n = 11, 8 wk) • No treatment	Histologic/biochemical/physiological: In 2 wk group, CST fibers regenerated for 2–11.4 mm; 8 wk group, CST fibers regenerated 2 mm into caudal spinal cord. Behavioral: Locomotor recovery in both IN-1/NT-3 groups was non-significant (was increased in 2 wk group for both AB treatment, but not significant, so behavioral recovery was mostly due to NT-3).
Z'Graggen et al., 1998	Model: female Lewis rats, 45−120 d old Injury: unilateral pyramidotomy	MAb IN-1 • Ab-secreting hybridoma implanted at 0 h PI	SCI + • IN-1 (n = 16) • Control Ab (n = 16) • Lesion only (n = 16) Sham + • IN-1 (n = 6) • No treatment (n = 6)	Histologic/biochemical/physiological: enhanced CST sprouting of the (corticopontine) and midline crossings Behavioral: enhanced recovery in grasping
Bregman et al., 1995	Model: Lewis Rats, 6−8 wk old Injury: T7 over-hemisection	MAb IN-1 • Ab-secreting hybridoma implanted at 0 h PI HRP	SCI + • IN-1 (n = 23) • Control Ab (HRP, n = 22) • Lesion only (n = 16) • Unlesioned control (n = 16)	Histologic/biochemical/physiological: Sprouting of CST fibers at lesion site, regeneration up to 11 mm within 3 wk, and these axons were maintained up to 12 wk later. IN-1 greatly increased serotonergic and noradrenergic projections. Behavioral: recovery in stride length; recovery of specific reflex (contact-placing response) and locomotor functions after spinal cord injury in these adult rats
Schnell and Schwab, 1990	Model: Lewis rats, 2−6 wk old Injury: T5-7 dorsal hemisection	MAb IN-1 • Ab-secreting hybridoma implanted at 0 h PI into dorsal fronto-parietal cortex with cyclosporin A, given 7−10 d pre-injury and continuous for a few weeks HRP • Via implanting antibody-secreting hybridoma cell injected into dorsal fronto-pariental cortex with cyclosporin A, given 7−10 d pre-injury and continuous for a few weeks	SCI + • IN-1 (n = 9) • HRP hybridoma cells (n = 2) • Non-treated control (n = 3)	Histologic/biochemical/physiological: sprouting of CST fibers at lesion site; regeneration up to 11 mm within 3 wk Behavioral: not reported

Ab, antibody; BBB, Basso, Beattie and Bresnahan locomotor test; C5, cervical vertebra 5; CGRP, calcitonin gene related protein; CSF, cerebrospinal fluid; CST, cortico-spinal tract; HRP, horseradish peroxidase; KO, knockout; MEP, motor-evoked potentials; PI, post-injury; SCI, spinal cord injury; SD rats, Sprague-Dawley rats; T8, thoracic vertebra 8.