Table 2.

Application of Pre-Clinical Grading System to Erythropoietin

					Clinically meaningful efficacy
					Thoracic SCI model		Cervical SCI model
Author		Animal species	Injury model	Maximum time window of efficacy	BBB Scores: Plantar wt support or coordination	Other motor and non-motor improvement	Motor improvement	Non-motor improvement	Dose response	Reproducibility/replication
1	Guízar-Sahagún Spinal Cord, 2009	Rats4	T9 contusion	0 h						Negative 1
2	Huang J. Int. Med. Res., 2009	Rats	T10 contusion3	0 h						Positive 1
3	Kontogeorgakos Arch. Orthop. Trauma Surg., 2009	Rats	T10 Clip3 compression	0 h					1000 IU/kg42 vs. 13 doses	Positive 2
4	Yazihan Injury, 2009	Rats	T9–11 Clip compression	1 h						Positive 3
5	Fumagalli Eur. J. Pharmacol., 2008	Rats	T9 contusion	30 min2	Coordination4					Positive 4
6	Mann Exp. Neurol., 2008	Rats	T9/10 Contusion	1 h tested						Negative 2
7	Pinzon Exp. Neurol., 2008	Rats	T3 Clip compression and T9 contusion	0 h, 24 h, or 48 h tested						Negative 3
8	Vitellaro-Zuccarello Neuroscience, 2008	Rats	T9 Contusion	30 min	Plantar WS and coordination					Positive (same as 5)
9	King Eur. J. Neurosci., 2007	Rats	T10/11 Hemisection	30 min						Positive 5
10	Okutan J. Clin. Neurosci., 2007	Rats	T9 Contusion	0 h						Positive 6
11	Vitellaro-Zuccarello Neuroscience, 2007	Rats	T9 Contusion	30 min	Plantar WS and coordination					Positive (same as 5)
12	Arishima Spine, 2006	Rats	T9 Weight compression	15 min						Positive 7
13	Cetin Eur. Spine J., 2006	Rats	T3 Clip compression	40 min		Swimming4			1000 IU/kg 1 vs. 3 doses	Positive 8
14	Grasso J. Neurosurg. Spine, 2006	Rats	T3 Clip Compression	0 h	Coordination					Positive (same as 17)
15	Boran Restor. Neurol. Neurosci., 2005	Rats	T6/7 Contusion	1 h		Swimming				Positive 9
16	Gorio PNAS, 2005	Rats	T9 Contusion	30 min					100, 500, 5000 IU/kg	Positive (same as 5)
17	Brines PNAS, 2004	Mice2	T3 Compression	0 h		BMS				Positive (same as 5)
18	Kaptanoglu Neurosurg. Rev., 2004	Rats	T8 Contusion	1 h						Positive (same as 10)
19	Gorio PNAS, 2002	Rats	T3 Clip Compresion and T9 contusion	1 h3	Coordination				500 vs. 5000 IU/kg	Positive (same as 5)
Scores		4 + 2 = 6	3 + 3 = 6	2 + 3 = 5	4	4			4	12–7 = 5
TOTAL						34

In the Vitellaro-Zuccarello studies, the EPO-treated animals achieved BBB scores ∼15, while the controls were ∼8, indicating that the treated animals achieved both weight support and consistent forelimb–hindlimb coordination while the controls did not achieve weight support in stance. Histologic improvements were also reported in both studies.

In the Fumagalli study, the BBB scores were 13.9 versus 9.5 for EPO versus control. Given that 14 is “consistent” forelimb–hindlimb coordination, we felt that the treated animals earned the score of for achieving coordination. In the Gorio 2005 paper, however, the BBB scores were 13 versus 9, and we therefore would not assign this as being “clinically meaningful” as per the BBB criteria because both groups achieved weight support, but the EPO animals did not achieve consistent forelimb–hindlimb coordination.

For reproducibility, the studies in which Gorio and Brines were involved were viewed as one independent lab, hence the positive studies of Fumagalli, Vitellaro-Zuccarello, Gorio, and Brines counted as one. With this, there were nine independent reports demonstrating positive effects of EPO (earning it a score of 12), and three independent reports of negative effects (earning it a score of (7). Hence, the final score is 5.