VALPROIC ACID IN AMBULANT ADULTS WITH SMA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本研究的主要目的是通过一项前瞻性、随机化、两阶段交叉、双盲、安慰剂对照试验，确定丙戊酸（VPA）口服给药6个月是否会改善脊髓性肌萎缩症（SMA）成人患者的力量和功能。 该研究将涉及36名患者，全部在俄亥俄州州入组。 受试者将被随机分配接受VPA或安慰剂治疗前6个月，之后患者将被交叉至另一组（即，所有患者将接受至少六个月的药物治疗）。 所有受试者将每隔3个月（3、6、9和12个月）进行评价，主要结局是通过计算机化肌肉测试评估的肌肉力量变化。 检查的次要结局包括肺功能、通过定时步行、爬楼梯和经验证的功能评定量表评估的运动功能、生活质量问卷、电生理参数、疾病的遗传和生化标志物（即运动神经元存活mRNA和蛋白质水平）以及通过双能X线吸收测定法评估的肌肉质量。 该研究基于这样的假设，即组蛋白脱乙酰酶抑制剂如VPA上调SMN 2的基因表达，这可以部分补偿导致疾病的SMN 1基因缺失。 这项研究的积极结果不仅将为SMA提供第一个有效的治疗方法，而且还将为这种方法提供“原则证明”，并导致这种疾病的进一步临床试验。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary objective of the study is to determine through a prospective, randomized, two-period crossover, double- blinded, placebo- controlled trial whether valproic acid (VPA) given orally for six months will improve strength and function in adult patients with spinal muscular atrophy (SMA). The study will involve 36 patients, all to be enrolled at Ohio State. Subjects will be randomly assigned to receive VPA or placebo for the first six months following which patients will be crossed over to the other group (i.e., all patients will receive drug for at least six months). All subjects will be evaluated at three months intervals (3, 6, 9 and 12 months), with the primary outcome being change in muscle strength assessed through computerized muscle testing. Secondary outcomes to be examined include pulmonary function, motor function assessed through timed walking, stair clinbing, and a validated functional rating scale, quality of life questionaire, electrophysiologic parameters, genetic and biochemical markers for the disease (ie survival motor neuron mRNA and protein levels), and muscle mass as assesssed through dual energy x-ray absorptiometry. The study is based on the hypothesis that histone deacetylase inhibitors like VPA up regulate gene expression of SMN2, which can partially compensate for the SMN1 gene deletion that causes the disease. A positive result in this study will not only provide the first effective treatment for SMA, but will also provide proof of principle" for this approach and lead to further clinical trials in this disorder.