STUDY OF SODIUM PHENYLBUTYRATE IN PEDIATRICS SUBJECTS WITH TYPE II/III SMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 脊髓性肌萎缩症(SMA)是一种常染色体隐性遗传病，其特征是脊髓前角细胞变性，导致弥漫性无力。在超过94%的SMA病例中发现存活运动神经元1基因(SMN1)的纯合子缺失，无论其亚型如何。SMN1位于染色体5q上的重复倒置区。SMN1的一个几乎相同的拷贝，命名为SMN2，包含一个单核苷酸变化，改变剪接并降低外显子7的整合效率，导致功能蛋白表达减少。然而，SMN2转录产生一小部分全长SMN mRNA。SMN拷贝数的增加，以及由此导致的功能蛋白表达的增加，与不那么严重的人类疾病和SMN基因敲除小鼠的表型拯救有关。几种化合物上调SMN2的表达或改变基因剪接，以产生全长与外显子7缺失的SMN mRNA的比率增加。一些化合物可用于人体，并在治疗其他疾病方面有被证明的安全记录，例如尿素循环障碍患者的苯丁酸钠(NaPB)。在SMA患者的成纤维细胞培养中，NaPB治疗导致全长SMN转录本增加。在SMA小鼠模型中，丁酸钠导致脊髓运动神经元SMN表达增加，并改善表型严重程度。在这里，我们建议通过监测与使用NaPB相关的剂量限制毒性(DLTS)来确定患有SMA II/III型的儿科受试者使用NaPB的最大耐受量(MTD)。

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. Spinal Muscular Atrophy (SMA) is an autosomal recessive disease characterized by degeneration of spinal cord anterior horn cells resulting in diffuse weakness. Homozygous deletion of the survival motor neuron 1 gene (SMN1) is found in more than 94% of SMA cases regardless of subtype. SMN1 resides in a duplicated inverted region on chromosome 5q. A near identical copy of SMN1, designated SMN2, contains a single nucleotide change which alters splicing and reduces the efficiency by which exon 7 is incorporated, leading to decreased functional protein expression. However, SMN2 transcription produces a small percentage of full length SMN mRNA. An increased number of SMN2 copies, with the resulting increase in functional protein expression, is associated with a less severe human disease and phenotypic rescue in the SMN knockout mouse. Several compounds up-regulate SMN2 expression or alter gene splicing to produce an increased ratio of full length to exon-7-deleted SMN mRNA. Some compounds are available for use in humans and have a proven safety record in treatment of other disorders, such as sodium phenylbutyrate (NaPB) in patients with urea cycle disorders. In fibroblast cultures from SMA patients, NaPB treatment causes an increase in full-length SMN transcripts. In the SMA mouse model, sodium butyrate causes increased SMN expression in spinal cord motor neurons and ameliorates the phenotypic severity. Here we propose to identify the maximum tolerated dose (MTD) of NaPB in pediatric subjects with SMA Type II/III by monitoring dose limiting toxicities (DLTs) associated with administration of NaPB.