异体间充质干细胞改善衰老虚弱：一项II期随机、双盲、安慰剂对照临床试验。
Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial.
作者信息
Tompkins Bryon A, DiFede Darcy L, Khan Aisha, Landin Ana Marie, Schulman Ivonne Hernandez, Pujol Marietsy V, Heldman Alan W, Miki Roberto, Goldschmidt-Clermont Pascal J, Goldstein Bradley J, Mushtaq Muzammil, Levis-Dusseau Silvina, Byrnes John J, Lowery Maureen, Natsumeda Makoto, Delgado Cindy, Saltzman Russell, Vidro-Casiano Mayra, Da Fonseca Moisaniel, Golpanian Samuel, Premer Courtney, Medina Audrey, Valasaki Krystalenia, Florea Victoria, Anderson Erica, El-Khorazaty Jill, Mendizabal Adam, Green Geoff, Oliva Anthony A, Hare Joshua M
机构信息
The Interdisciplinary Stem Cell Institute.
Department of Surgery.
出版信息
J Gerontol A Biol Sci Med Sci. 2017 Oct 12;72(11):1513-1522. doi: 10.1093/gerona/glx137.
BACKGROUND
Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair.
METHODS
This is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion.
RESULTS
No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p = .01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in both the 100M- (p < .0001) and 200M-groups (p = .002) as well as between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy.
CONCLUSION
Intravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder.
CLINICAL TRIAL REGISTRATION
www.clinicaltrials.gov: CRATUS (#NCT02065245).
背景
衰老虚弱以身体和免疫功能下降为特征，与干细胞耗竭有关。人同种异体间充质干细胞（allo-hMSCs）具有免疫调节作用并促进组织修复。
方法
这是一项随机、双盲、剂量探索性研究，将静脉注射的allo-hMSCs（1亿或2亿个）与安慰剂给予虚弱患者（n = 30，平均年龄75.5±7.3岁）。主要终点是输注后1个月出现的治疗中严重不良事件（TE-SAEs）的发生率。次要终点包括输注后6个月时的身体功能、患者报告的结局以及虚弱的免疫标志物。
结果
1个月时未发生与治疗相关的TE-SAEs。1亿个细胞组的身体功能优先改善；1亿个细胞组和2亿个细胞组的免疫功能均有改善。1亿个细胞组的6分钟步行试验、简短身体功能检查和1秒用力呼气量有所改善（p = 0.01），2亿个细胞组或安慰剂组则无改善。1亿个细胞组的女性性生活质量问卷有所改善（p = 0.03）。1亿个细胞组的血清TNF-α水平下降（p = 0.03）。1亿个细胞组（p < 0.0001）和2亿个细胞组（p = 0.002）以及与安慰剂组相比，两组之间的B细胞内TNF-α均有改善（分别为p = 0.003和p = 0.039）。MSC治疗还可减少早期和晚期活化T细胞。
结论
静脉注射allo-hMSCs对衰老虚弱个体是安全的。治疗组在身体功能指标和炎症生物标志物方面有显著改善，这两者都是虚弱综合征的特征。鉴于本研究显示出的出色安全性和疗效，有必要进行更大规模的临床试验以确定hMSCs在这种多系统疾病中的疗效。
临床试验注册
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