G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial

BackgroundThe hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and -regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.
MethodsTen patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 µg/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints.
Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.
ResultsTreatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.
ConclusionsSubcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors.
Trial RegistrationClinicalTrials.gov NCT00298597

【背景】造血蛋白粒细胞集落刺激因子（Granulocyte-colony stimulating factor, G-CSF）具备神经保护与神经再生特性。G-CSF受体由运动神经元表达，且G-CSF可保护培养的运动神经元细胞免于凋亡，因此其成为治疗肌萎缩侧索硬化（amyotrophic lateral sclerosis, ALS）的极具吸引力且可行的药物候选者。本项预试验旨在明确ALS患者接受G-CSF治疗是否具备可行性。
【方法】10名确诊ALS的患者纳入本项双盲、安慰剂对照随机试验。患者在研究前10天以及研究第20至25天，皮下注射10 µg/kg体重（Body Weight, BW）的G-CSF或安慰剂。临床结局通过ALS功能评定量表（ALS functional rating scale, ALSFRS）的变化、一套全面的神经心理学测试组合，以及评估研究全程（100天）内的日常手部活动进行评估。安全性终点包括不良事件（adverse event, AE）总数、治疗相关不良事件、因治疗相关不良事件停药的情况、白细胞、红细胞、血小板计数等实验室指标，以及生命体征。此外，本研究基于弥散张量成像（Diffusion Tensor Imaging, DTI）的体素级统计分析、脑容积测量及基于体素的形态测量学（voxel-based morphometry），探究了G-CSF对脑部结构性异常的潜在影响。
【结果】治疗耐受性良好。从基线至第100天，两组间的临床测试结果与脑容积测量结果均无显著差异。然而，DTI分析显示，与对照组相比，患者组的各向异性分数（fractional anisotropy, FA）在脑部弥散区域出现显著降低。纵向分析表明，安慰剂组的FA下降幅度更大、范围更广，较接受G-CSF治疗的ALS患者更为显著。
【结论】ALS患者接受皮下G-CSF治疗是一种可行的方案。尽管临床数据的探索性分析未显示显著疗效，但DTI测量结果提示，ALS中广泛且进行性的微结构神经损伤可通过G-CSF治疗得到调控。上述发现对后续开展基于生长因子的ALS临床试验具有重要参考价值。
【试验注册】ClinicalTrials.gov NCT00298597