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Compassionate Use of the ROCK Inhibitor Fasudil in Three Patients With Amyotrophic Lateral Sclerosis.

富有同情心地使用 ROCK 抑制剂法舒地尔治疗 3 例肌萎缩侧索硬化患者。

  • 影响因子:2.99
  • DOI:10.3389/fneur.2020.00173
  • 作者列表:"Koch JC","Kuttler J","Maass F","Lengenfeld T","Zielke E","Bähr M","Lingor P
  • 发表时间:2020-03-13
Abstract

:The Rho kinase (ROCK) inhibitor Fasudil is a promising drug for a disease-modifying therapy of amyotrophic lateral sclerosis (ALS). In preclinical models, Fasudil was shown to increase motor neuron survival, inhibit axonal degeneration, enhance axonal regeneration and modulate microglial function in vitro and in vivo. It prolonged survival and improved motor function of SOD1-G93A-mice. Recently, a phase IIa clinical trial has been commenced to investigate the safety, tolerability, and efficacy of Fasudil in ALS patients at an early stage of disease (ROCK-ALS trial, NCT03792490, Eudra-CT-Nr.: 2017-003676-31). Although Fasudil has been approved in Japan for many years for the treatment of vasospasms following subarachnoid hemorrhage and is known to have a favorable side effect profile in these patients, there is no data on its use in human patients with ALS or any other neurodegenerative conditions. Here, we report the first three cases of compassionate use of Fasudil in patients with ALS. Between May 2017 and February 2019, one male (66 years old) and two female (62 and 68 years old) subjects with probable or definite ALS according to the El Escorial criteria (one of the females having a pathogenic SOD1 mutation) were administered Fasudil 30 mg intravenously twice daily over 45 min on 20 consecutive working days. Blood pressure, heart rate and routine laboratory tests were constantly controlled. All three subjects tolerated the Fasudil infusions well without any obvious side effects. Interestingly, the slow vital capacity showed a significant increase in one of the patients. Taken together, we report here the first compassionate use of the ROCK inhibitor Fasudil in three ALS patients, which was well-tolerated.

摘要

: Rho 激酶 (ROCK) 抑制剂法舒地尔是一种有希望用于肌萎缩侧索硬化 (ALS) 疾病缓解治疗的药物。在临床前模型中,法舒地尔在体内外表现出增加运动神经元存活、抑制轴突变性、增强轴突再生和调节小胶质细胞功能的作用。延长了 SOD1-G93A-mice 的存活时间,改善了运动功能。最近,一项 IIa 期临床试验已经开始,以研究法舒地尔在疾病早期阶段对 ALS 患者的安全性、耐受性和疗效 (ROCK-ALS 试验,nct048/2490,eudra-CT-Nr.:2017-003676-31)。虽然法舒地尔在日本已被批准用于治疗蛛网膜下腔出血后的血管痉挛多年,并且已知在这些患者中有良好的副作用,没有关于其在 ALS 或任何其他神经退行性疾病的人类患者中的使用数据。在此,我们报告了 ALS 患者同情使用法舒地尔的前三例。2017年5月 08 年 2019年2月期间,1 名男性 (66 岁) 和 2 名女性 (62 岁和 68 岁) 根据 El Escorial 标准可能或明确 ALS 的受试者 (其中一名女性有致病性 SOD1 突变)给予法舒地尔 30 mg 静脉注射,每日两次,每次 45 min,连续 20 个工作日。血压、心率和常规实验室检查得到持续控制。所有 3 例受试者对法舒地尔输注耐受良好,无任何明显副作用。有趣的是,缓慢的肺活量在其中一名患者中显示出显著增加。总之,我们在这里报告了 ROCK 抑制剂法舒地尔在 3 例 ALS 患者中的首次使用,耐受性良好。

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翻译标题与摘要 下载文献
影响因子:3.92
发表时间:2020-01-01
DOI:10.1111/bpa.12761
作者列表:["Sebastián-Serrano Á","Simón-García A","Belmonte-Alfaro A","Pose-Utrilla J","Santos-Galindo M","Del Puerto A","García-Guerra L","Hernández IH","Schiavo G","Campanero MR","Lucas JJ","Iglesias T"]

METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.

翻译标题与摘要 下载文献
影响因子:3.66
发表时间:2020-01-24
DOI:10.3233/JAD-191069
作者列表:["Mendes FR","Leclerc JL","Liu L","Kamat PK","Naziripour A","Hernandez D","Li C","Ahmad AS","Doré S"]

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