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Journal of Neurorestoratology  2020, Vol. 8 Issue (3): 182-193    doi: 10.26599/JNR.2020.9040019
Research Article     
Olfactory ensheathing cells in chronic ischemic stroke: A phase 2, double-blind, randomized, controlled trial
Yunliang Wang1,12, Xiaoling Guo2, Jun Liu3, Zuncheng Zheng4, Ying Liu5,6, Wenyong Gao5,6, Juan Xiao5,6, Yanqiu Liu1, Yan Li2, Manli Tang3, Linlin Wang7, Lin Chen8, Di Chen6, Deqiang Guo9, Fei Liu9, Weidong Chen10, Baomin Chan11, Bo Zhou2, Aibing Liu5, Gengsheng Mao5, Hongyun Huang5,6,(✉)
1 Neurological Center, 960 Hospital of Chinese PLA, Zibo 255300, Shandong, China
2 Neurological Department, 981 Hospital of Chinese PLA, Chengde 067000, Hebei, China
3 Neurological Department, Civil Aviation Guangzhou Hospital, Guangzhou 510405, Guangdong, China
4 Department of Rehabilitation, Taian Central Hospital, Taian 271000, Shandong, China
5 Institute of Neurorestoratology, Third Medical Center of General Hospital of PLA, Beijing 100039, China
6 Beijing Hongtianji Neuroscience Academy, Beijing 100143, China
7 Institute of Reproductive and Child Health/National Health Commission Key Laboratory of Reproductive Health, School of Public Health, Peking University Health Science Center, Beijing 100191, China
8 Department of Neurosurgery, Dongzhimen Hospital of Beijing University of Traditional Chinese Medicine, Beijing 100700, China
9 E.N.T. Department, 960 Hospital of Chinese PLA, Zibo 255300, Shandong, China
10 E.N.T. Department, 981 Hospital of Chinese PLA, Chengde 067000, Hebei, China
11 E.N.T. Department, Civil Aviation Guangzhou Hospital, Guangzhou 510405, Guangdong, China
12 Neurological Department, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, Henan, China
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Abstract  

Olfactory ensheathing cells (OECs) have shown promising results for patients with neurologic diseases in non-double-blind, placebo control studies. Thirty patients with a unilateral ischemic stroke of more than a year were enrolled in a phase 2, multicenter, randomized, double-blind, and placebo-controlled cell therapy trial with a subsequent 12-month follow-up. The primary therapeutic objective has shown that after 12 months, there were significant differences in National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) assessment scores among the OEC group, Schwann cell group and placebo medium group at one-year follow-up. The second therapeutic objective found that there were significant differences in NIHSS, mRS, and BI assessment scores when comparing the endpoint data with the baseline data in the OEC group. There was neither hypersensitivity reaction nor adverse event. The results of this multicenter, randomized, double-blind, and placebo-controlled study indicate that injecting OECs into the olfactory sub-mucosa have neurorestorative effects, which can improve the quality of life for patients with chronic ischemic strokes without serious side effects.



Key wordsolfactory ensheathing cells      Schwann cells      chronic ischemic stroke      cell therapy      randomized control trial     
Received: 27 July 2020      Published: 28 September 2020
Corresponding Authors: Hongyun Huang   
Cite this article:

Yunliang Wang, Xiaoling Guo, Jun Liu, Zuncheng Zheng, Ying Liu, Wenyong Gao, Juan Xiao, Yanqiu Liu, Yan Li, Manli Tang, Linlin Wang, Lin Chen, Di Chen, Deqiang Guo, Fei Liu, Weidong Chen, Baomin Chan, Bo Zhou, Aibing Liu, Gengsheng Mao, Hongyun Huang. Olfactory ensheathing cells in chronic ischemic stroke: A phase 2, double-blind, randomized, controlled trial. Journal of Neurorestoratology, 2020, 8: 182-193.

URL:

http://jnr.tsinghuajournals.com/10.26599/JNR.2020.9040019     OR     http://jnr.tsinghuajournals.com/Y2020/V8/I3/182

Fig. 1A otolaryngologist was preparing to do injection.
Fig. 2Before (A) and after (B) cell culture medium injecting into sub-mucosa, local tissue looks plump.
Fig. 3Diagram of cell injection and migration. After cell being injected into sub-mucosa of olfactory area, they migrated into olfactory bulb and then to lesion area.
Fig. 4Study flow diagram.
Baseline characteristicsPlacebo group (n = 9)OEC group (n = 9)SC group (n = 9)P valuea
Age in years mean ± SD63.56 ± 4.3660.67 ± 4.5356.89 ± 7.720.066
Sex, males number (percentage)5 (55.56%)7 (77.78%)8 (88.89%)0.259
History of stroke in months median (IQR)21.00 (13.00, 35.00)27.00 (14.50, 52.00)28.00 (18.50, 39.00)0.643
NIHSS score median (IQR)5.00 (4.00, 6.50)4.00 (4.00, 6.00)5.00 (4.00, 11.50)0.878
mRS score median (IQR)3.00 (2.00, 4.00)3.00 (2.50, 4.00)2.00 (1.50, 3.00)0.243
BI score median (IQR)85.00 (50.00, 90.00)65.00 (47.50, 82.50)90.00 (55.00, 92.50)0.222
Table 1Baseline characteristics.
Assessment scoresPlacebo group (n = 9)OEC group (n = 9)SC group (n = 9)Test statisticP valuea
NIHSS, median (IQR)0.00 (0.00, 0.00)?3.00 (?4.50, ?0.50)**?1.00 (?2.00, 0.00)8.8420.012
mRS, median (IQR)0.00 (0.00, 0.00)?1.00 (?1.50, 0.00)0.00 (0.00, 0.00)#6.6930.035
BI, median (IQR)0.00 (0.00, 0.00)15.00 (2.50, 27.50)**0.00 (0.00, 5.00)10.5090.005
Table 2Comparison of changes in assessment scores at 12 months after treatment.
Assessment scoresPlacebo group (n = 9)OEC group (n = 9)SC group (n = 9)Kruskal-Wallis test statisticP valuea
NIHSS, median (IQR)0.00 (0.00, 0.00)?1.00 (?2.50, 0.00)0.00 (?0.50, 0.00)4.9530.084
mRS, median (IQR)0.00 (0.00, 0.00)0.00 (?0.50, 0.00)0.00 (?0.50, 0.00)0.4730.789
BI, median (IQR)0.00 (0.00, 0.00)5.00 (0.00, 10.00)0.00 (0.00, 0.00)#9.2960.010
Table 3Comparison of changes in assessment scores at 3 months after treatment.
Assessment scoresPlacebo group (n = 9)OEC group (n = 9)SC group (n = 9)Kruskal-Wallis test statisticP value a
NIHSS, median (IQR)0.00 (0.00, 0.00)?3.00 (?3.50, ?0.50)**?1.00 (?1.50, 0.00)9.1180.010
MRS, median (IQR)0.00 (0.00, 0.00)?1.00 (?1.50, 0.00)0.00 (0.00, 0.00)6.5010.039
BI, median (IQR)0.00 (0.00, 0.00)15.00 (2.50, 27.50)**0.00 (0.00, 2.50)#12.2410.002
Table 4Comparison of changes in assessment scores at 6 months after treatment.
Assessment scoresBaseline1 month3 months6 months1 year
Median (IQR)Median (IQR)P valueMedian (IQR)P valueMedian (IQR)P valueMedian (IQR)P value
NIHSS4.00 (4.00, 6.00)4.00 (3.50, 6.00)0.1024.00 (2.50, 5.50)0.0423.00 (2.00, 4.50)0.0173.00 (1.00, 4.50)0.018
mRS3.00 (2.50, 4.00)3.00 (2.50, 4.00)1.0003.00 (2.00, 3.50)0.1572.00 (2.00, 3.00)0.0382.00 (2.00, 3.00)0.038
BI65.00 (47.50, 82.50)65.00 (50.00, 82.50)0.31770.00 (55.00, 85.00)0.03485.00 (72.50, 95.00)0.01885.00 (72.50, 95.00)0.018
Table 5Neurorestorative effects in OEC treatment.
Assessment scoresBaseline1 month3 months6 months1 year
Median (IQR)Median (IQR)P valueMedian (IQR)P valueMedian (IQR)P valueMedian (IQR)P value
NIHSS5.00 (4.00, 11.50)4.00 (4.00, 11.50)0.3174.00 (4.00, 11.50)0.1574.00 (3.00, 11.00)0.0234.00 (3.00, 11.00)0.024
mRS2.00 (1.50, 3.00)2.00 (1.00, 3.00)0.3172.00 (1.00, 3.00)0.1572.00 (1.00, 3.00)0.3172.00 (1.00, 3.50)1.000
BI90.00 (55.00, 92.50)90.00 (55.00, 92.50)1.00090.00 (55.00, 92.50)1.00090.00 (55.00, 95.00)0.15795.00 (57.50, 95.00)0.046
Table 6Neurorestorative effects in SC treatment.
Assessment scoresBaseline1 month3 months6 monthsOne year
Median (IQR)Median (IQR)P ValueMedian (IQR)P ValueMedian (IQR)P ValueMedian (IQR)P Value
NIHSS5.00 (4.00, 6.50)5.00 (4.00, 6.50)1.0005.00 (4.00, 6.50)0.3175.00 (4.00, 6.50)0.3175.00 (4.00, 6.50)0.317
mRS3.00 (2.00, 4.00)3.00 (2.00, 4.00)1.0003.00 (2.00, 3.50)0.3173.00 (2.00, 3.50)0.3173.00 (2.00, 3.50)0.317
BI85.00 (50.00, 90.00)85.00 (50.00, 90.00)1.00085.00 (50.00, 90.00)0.31785.00 (50.00, 90.00)0.31785.00 (52.50, 90.00)0.317
Table 7Neurorestorative effects in medium treatment.
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