SMA is a genetically determined motor system disorder that results in muscle weakness, selective motor neuron death, muscle atrophy, and impaired functional mobility. In SMA model systems, long-term treatment with 4-aminopyridine (4-AP) has been shown to improve motor function. To assess tolerability and preliminary efficacy of 4-AP on walking ability, endurance and EMG in adult ambulatory SMA patients, we conducted a double blind, placebo control, crossover pilot study with dalfampridine (4-AP, 10 mg BID). The study is comprised of a short-term (2 weeks) treatment arm with 1-week washout and a long-term (6 weeks) treatment arm with a 2-week washout. The primary outcome measure, for which the study was powered, was the 6 min walk test (6MWT, distance and percent fatigue); secondary outcome measures were the Hammersmith Functional Motor Scale Expanded (HFMSE), Manual Muscle Testing (MMT), Myometry with Hand held Dynamometry, HHD) and Quantitative Gait Analyses. We performed electrophysiology, including CMAP and H-reflex, during the short-term treatment trial. The mean age of the 11 participants enrolled was 37.7 ± 11.9 years; 54.5% were male. Dalfampridine was safe and well tolerated and no patient suffered a serious adverse event related to treatment. We observed no statistically significant positive effects of dalfampridine treatment on our primary functional motor outcome (6MWT distance, fatigue). Dalfampridine had a positive effects on H-reflex and H/M ratio but not on CMAP amplitude. The effect on the H-reflex is of interest, as it suggests dalfampridine may enhance neuronal activity, an effect observed in SMA Drosophila and mouse models at doses (mg/kg) not recommended for clinical use. Larger studies with dalfampridine in SMA patients are needed to confirm our findings, especially in light of studies in other populations showing drug effects in only a subset of patients.

中文翻译：

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对成人 SMA 患者的 dalfampridine-ER (4-AP) 治疗缺乏影响。

SMA 是一种由基因决定的运动系统疾病，会导致肌肉无力、选择性运动神经元死亡、肌肉萎缩和功能活动受损。在 SMA 模型系统中，4-氨基吡啶 (4-AP) 的长期治疗已被证明可以改善运动功能。为了评估 4-AP 对成人非卧床 SMA 患者的步行能力、耐力和 EMG 的耐受性和初步疗效，我们进行了一项双盲、安慰剂对照、交叉试验研究，其中包括 dalfampridine（4-AP，10 mg BID）。该研究由具有 1 周洗脱期的短期（2 周）治疗组和具有 2 周洗脱期的长期（6 周）治疗组组成。该研究的主要结果指标是 6 分钟步行测试（6MWT、距离和疲劳百分比）；次要结果测量是扩展的 Hammersmith 功能性运动量表 (HFMSE)、手动肌肉测试 (MMT)、手持测力法测力法 (HHD) 和定量步态分析。我们在短期治疗试验期间进行了电生理学检查，包括 CMAP 和 H 反射。11 名参与者的平均年龄为 37.7 ± 11.9 岁；54.5% 是男性。Dalfampridine 安全且耐受性良好，没有患者出现与治疗相关的严重不良事件。我们没有观察到 dalfampridine 治疗对我们的主要功能性运动结果（6MWT 距离、疲劳）有统计学意义的积极影响。Dalfampridine 对 H 反射和 H/M 比有积极影响，但对 CMAP 幅度没有积极影响。对 H 反射的影响很有趣，因为它表明 dalfampridine 可以增强神经元活动，在不推荐用于临床使用的剂量 (mg/kg) 下，在 SMA 果蝇和小鼠模型中观察到的效果。需要在 SMA 患者中使用 dalfampridine 进行更大规模的研究来证实我们的发现，特别是考虑到其他人群的研究仅显示对一部分患者的药物作用。