Spinal muscular atrophy: Mechanisms & treatment strategies.

脊髓性肌萎缩症：机制

• 批准号: 10308474
• 负责人: Umrao Monani
• 金额: $ 39.66万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308474
• 关键词: Achievement; Address; Adverse effects; Behavioral; Behavioral Assay; Biology; Cells; Cessation of life; Chromosome 9; Chronic; Clinical; Clinical Trials; Data; Defect; Development; Diagnosis; Disease; Evaluation; FDA approved; Generations; Genes; Genetic Screening; Health; Human; Individual; Infant; Infant Mortality; Inherited; Institution; Investigation; Late-Onset Disorder; Length; Light; Long-Term Effects; Mediating; Mediator of activation protein; Mind; Molecular; Molecular Analysis; Molecular Chaperones; Morphology; Motor Neurons; Mouse Protein; Mus; Muscle; Mutate; Mutation; Myopathy; Nerve; Neuromuscular Diseases; Onset of illness; Outcome; Paralysed; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Proteins; Protocols documentation; RNA Splicing; Reporting; Research; Rest; Risk; Rodent; SMN protein (spinal muscular atrophy); SMN1 gene; SMN2 gene; Skeletal Muscle; Spinal; Spinal Muscular Atrophy; Therapeutic; Time; Tissues; Transcript; Translating; Validation; base; clinically relevant; disease phenotype; effective therapy; experimental study; molecular array; mortality; mouse model; mutant; neuromuscular system; neuron loss; novel; optimism; premature; prevent; stem; treatment effect; treatment strategy

Project Summary Spinal muscular atrophy (SMA) is a common, frequently fatal, neuromuscular disorder caused by mutations in the Survival of Motor Neuron 1 (SMN1) gene and, consequently, a paucity of the SMN protein. In humans, an almost identical copy gene, SMN2, is unable to fully compensate for loss of SMN1 owing to a splicing defect and thus an inability to express sufficient protein to stave off disease. In the two decades that we have researched SMA much progress has been made, from the identification of the disease gene and the description of its protein to the generation of pre-clinical models and, most recently, the approval of Spinraza, a promising drug that raises SMN levels and thus thwarts the inevitable paralysis and frequent death associated with SMA. While Spinraza, in particular, raises considerable optimism for SMA patients, significant challenges remain and, in our minds, stem from two crucial deficiencies. First, despite the milestones achieved, how low SMN protein evolves into the SMA phenotype, selectively triggering motor neuron death and preferentially disabling the neuromuscular system remains a singular mystery. This is especially perplexing considering SMN's most widely-cited function of orchestrating the splicing cascade. Identifying mediators that provide a logical explanation for why splicing defects cause SMA or, uncovering additional, more disease-relevant SMN functions is therefore not only mechanistically but also therapeutically relevant. Second, while it is clear that administering Spinraza provides immediate benefit to patients, it is premature to make a determination of the long-term outcome of such treatment; the drug is selectively delivered to the CNS, raising questions about the effects of chronic low SMN in the periphery. Besides, the strategy of raising SMN appears inadequate in the symptomatic patient. Here we describe 3 related sets of experiments that address the deficiencies identified above. Aim 1 proposes to define disease-relevant mechanisms by exploiting a novel line of SMA mice in which early mortality, motor neuron loss and a severe phenotype are replaced by prolonged survival, intact motor neurons and a decidedly mild phenotype. We hypothesize that a spontaneous mutation in a chaperone protein that the mice express suppresses the SMA phenotype. We will confirm and extend this finding to determine how the chaperone modulates the effects of low SMN. In aim 2, we will examine the potential long- term adverse effects of persistently low levels of SMN in muscles of model mice expressing normal protein in the CNS. Such rodents represent a pre-clinical model of SMA patients administered Spinraza. We propose that chronic low SMN in skeletal muscle has a profoundly negative impact on the health of the tissue and contributes to the overall SMA phenotype. In aim 3, we will determine if the disease-causing effects of low SMN in muscle can nevertheless be mitigated upon restoring protein post-symptomatically. Reversing such defects will inform the manner in which current treatments may have to be modified to prove more potent. Our study thus addresses important mechanistic as well as clinical aspects of SMA.

项目摘要 脊髓性肌萎缩症（SMA）是一种常见的，经常致命的，神经肌肉疾病引起的突变， 运动神经元1（SMN1）基因的生存，因此，缺乏SMN蛋白。在人类中， 几乎相同的拷贝基因SMN2不能完全补偿由于剪接缺陷而导致的SMN1的损失 因此不能表达足够的蛋白质来避免疾病。在过去的二十年里， SMA的研究已取得了很大的进展，从致病基因的鉴定， 它的蛋白质的描述，以产生临床前模型，最近，批准Spinraza， 一种很有前途的药物，可以提高SMN水平，从而阻止不可避免的瘫痪和与之相关的频繁死亡。 关于SMA虽然Spinraza特别为SMA患者带来了相当大的乐观情绪， 在我们看来，这仍然存在，而且源于两个关键的缺陷。首先，尽管取得了里程碑式的成就， SMN蛋白演变成SMA表型，选择性地触发运动神经元死亡， 使神经肌肉系统失效仍然是个谜这是特别令人困惑的考虑到 SMN最广泛引用的协调剪接级联的功能。确定提供 为什么剪接缺陷会导致SMA或发现其他疾病相关性更高的SMN 因此，功能不仅在机制上而且在治疗上相关。第二，虽然很明显， 尽管Spinraza给药可为患者提供直接获益，但确定其疗效还为时过早。 这种治疗的长期结果;药物被选择性地递送到CNS，引起了关于 外周慢性低SMN的影响。此外，提高SMN的战略在 有症状的病人在这里，我们描述了3组相关的实验，以解决所发现的缺陷 以上目的1提出通过开发一种新的SMA小鼠系来定义疾病相关机制， 其早期死亡、运动神经元损失和严重表型被延长的存活、完整的 运动神经元和明显温和的表型。我们假设伴侣蛋白的自发突变 小鼠表达的蛋白质抑制SMA表型。我们将确认并扩大这一发现， 确定分子伴侣如何调节低SMN的影响。在目标2中，我们将研究潜在的长期- 在表达正常蛋白质的模型小鼠肌肉中持续低水平的SMN的长期副作用， CNS。此类啮齿动物代表了Spinraza给药SMA患者的临床前模型。我们提出 骨骼肌中的慢性低SMN对组织的健康具有深刻的负面影响， 有助于整体SMA表型。在目标3中，我们将确定低剂量的 然而，肌肉中的SMN可以在术后恢复蛋白质后减轻。扭转这种 缺陷将告知当前治疗可能必须修改以证明更有效的方式。我们 因此，这项研究解决了SMA的重要机制和临床问题。

项目成果

Emerging concepts underlying selective neuromuscular dysfunction in infantile-onset spinal muscular atrophy.

婴儿性脊柱肌肉萎缩的选择性神经肌肉功能障碍的基础的新兴概念。

• DOI: 10.4103/1673-5374.308073
• 发表时间: 2021-10
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Gollapalli K;Kim JK;Monani UR
• 通讯作者: Monani UR

Muscle: an independent contributor to the neuromuscular spinal muscular atrophy disease phenotype.

• DOI: 10.1172/jci.insight.171878
• 发表时间: 2023-09-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Jha, Narendra N.;Kim, Jeong-Ki;Her, Yoon-Ra;Monani, Umrao R.
• 通讯作者: Monani, Umrao R.

Diminished muscle oxygen uptake and fatigue in spinal muscular atrophy.

• DOI: 10.1002/acn3.51353
• 发表时间: 2021-05
• 期刊: Annals of clinical and translational neurology
• 影响因子: 5.3
• 作者: Montes J;Goodwin AM;McDermott MP;Uher D;Hernandez FM;Coutts K;Cocchi J;Hauschildt M;Cornett KM;Rao AK;Monani UR;Ewing Garber C;De Vivo DC
• 通讯作者: De Vivo DC