Idebenone does not inhibit disability progression in primary progressive MS.
Idebenone does not inhibit disability progression in primary progressive MS.
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DOI：
10.1016/j.msard.2020.102434
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发表时间：
2020-10
影响因子：
4
通讯作者：
Bielekova, Bibiana
中科院分区：
文献类型：
--
作者：
Kosa, Peter;Wu, Tianxia;Phillips, Jonathan;Leinonen, Mika;Masvekar, Ruturaj;Komori, Mika;Wichman, Alison;Sandford, Mary;Bielekova, Bibiana
多发性硬化（MS）是一种慢性、免疫介导的中枢神经系统（CNS）神经退行性疾病。虽然目前的MS疗法靶向炎症过程，但没有治疗明确靶向线粒体功能障碍和导致的轴突损失。因此，本研究的目的是确定艾地苯醌是否抑制原发性进展性MS（PPMS）中的线粒体功能障碍和残疾积累，并使用脑脊液（CSF）生物标志物增强对PPMS进展的致病机制的理解。艾地苯醌在原发性进展型MS患者中的双盲、安慰剂对照I/II期临床试验（IPPoMS; NCT 00950248）是一项适应性设计、基线与治疗、安慰剂对照、CSF生物标志物支持的试验。基于1年治疗前数据的中期分析，组合权重调整残疾评分（CombiWISE）曲线下面积的变化成为主要结局，在基线与治疗模式下，28例患者/组治疗2年，检测≥40%疗效的把握度>80%。传统残疾量表和脑室容积的变化是次要结局。探索性结局包括线粒体功能障碍（生长/分化因子15 [GDF 15]和乳酸盐）、轴突损伤（神经丝轻链[NFL]）、先天性免疫（sCD 14）、血脑屏障渗漏（白蛋白商）和视网膜神经纤维层变薄的CSF生物标志物。艾地苯醌耐受性良好，但不能抑制残疾进展或CNS组织破坏。在体外主要由星形胶质细胞和脉络丛上皮分泌的GDF 15的浓度在暴露于线粒体毒素鱼藤酮后增加，验证了该生物标志物测量鞘内线粒体损伤的能力。CSF GDF 15水平与年龄密切相关，MS患者的CSF GDF 15水平显著高于年龄校正的健康志愿者，在PPMS中测得的水平最高。艾地苯醌未改变CSF GDF 15水平。线粒体功能障碍超过年龄调整的CSF GDF 15所反映的正常老化是目前在大多数PPMS患者，但它不抑制艾地苯醌。
Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder of the central nervous system (CNS). While current MS therapies target the inflammatory processes, no treatment explicitly targets mitochondrial dysfunction and resulting axonal loss. Therefore, the aim of this study was to determine whether idebenone inhibits mitochondrial dysfunction and accumulation of disability in primary progressive MS (PPMS) and to enhance understanding of pathogenic mechanisms of PPMS progression using cerebrospinal fluid (CSF) biomarkers. The double-blind, placebo-controlled Phase I/II clinical trial of Idebenone in patients with Primary Progressive MS (IPPoMS; NCT00950248) was an adaptively designed, baseline-versus-treatment, placebo-controlled, CSF-biomarker-supported trial. Based on interim analysis of the 1-year pre-treatment data, change in the area under the curve of Combinatorial Weight-Adjusted Disability Score (CombiWISE) became the primary outcome, with >80% power to detect ≥40% efficacy with 28 patients/arm treated for 2 years in baseline versus treatment paradigm. Changes in traditional disability scales and in brain ventricular volume were secondary outcomes. Exploratory outcomes included CSF biomarkers of mitochondrial dysfunction (Growth/differentiation factor 15 [GDF15] and lactate), axonal damage (neurofilament light chain [NFL]), innate immunity (sCD14), blood brain barrier leakage (albumin quotient) and retinal nerve fiber layer thinning. Idebenone was well tolerated but did not inhibit disability progression or CNS tissue destruction. Concentrations of GDF15, secreted predominantly by astrocytes and choroid plexus epithelium in vitro, increased after exposure to mitochondrial toxin rotenone, validating the ability of this biomarker to measure intrathecal mitochondrial damage. CSF GDF15 levels correlated strongly with age and MS patients had CSF levels of GDF15 significantly above age-adjusted healthy volunteers, with highest levels measured in PPMS. Idebenone did not change CSF GDF15 levels. Mitochondrial dysfunction exceeding normal aging reflected by age-adjusted CSF GDF15 is present in the majority of PPMS patients, but it is not inhibited by idebenone.
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DOI：
10.4049/jimmunol.1302884
发表时间：
2014-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Han S;Lin YC;Wu T;Salgado AD;Mexhitaj I;Wuest SC;Romm E;Ohayon J;Goldbach-Mansky R;Vanderver A;Marques A;Toro C;Williamson P;Cortese I;Bielekova B
通讯作者：
Bielekova B
影响因子：
5.8
作者：
Cadavid, Diego;Cohen, Jeffrey A.;Mikol, Daniel
通讯作者：
Mikol, Daniel
影响因子：
11.2
作者：
Barbour, Christopher;Kosa, Peter;Bielekova, Bibiana
通讯作者：
Bielekova, Bibiana
影响因子：
14.5
作者：
Mahad, Don J.;Ziabreva, Iryna;Turnbull, Douglass M.
通讯作者：
Turnbull, Douglass M.
影响因子：
11.2
作者：
Dutta, R;McDonough, J;Trapp, BD
通讯作者：
Trapp, BD