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.

项目概要 脊髓性肌萎缩症 (SMA) 是一种常见且常常致命的神经肌肉疾病，由脊髓性肌萎缩症 (SMA) 突变引起 运动神经元存活 1 (SMN1) 基因，因此导致 SMN 蛋白缺乏。在人类中，一个 几乎相同的拷贝基因 SMN2 由于剪接缺陷而无法完全补偿 SMN1 的损失 因此无法表达足够的蛋白质来预防疾病。在我们这二十年里 SMA的研究取得了很大进展，从致病基因的鉴定和 从对其蛋白质的描述到临床前模型的生成，以及最近 Spinraza 的批准， 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频繁死亡 与 SMA。尽管 Spinraza 特别为 SMA 患者带来了相当大的乐观情绪，但也面临着重大挑战 在我们看来，这种现象仍然存在，并且源于两个关键缺陷。首先，尽管取得了里程碑式的成就，但其水平有多低？ SMN蛋白进化成SMA表型，选择性触发运动神经元死亡并优先 使神经肌肉系统失去功能仍然是一个谜。考虑到这一点尤其令人困惑 SMN 最广泛引用的功能是协调拼接级联。识别中介者提供 合理解释为什么剪接缺陷会导致 SMA，或者发现更多与疾病相关的 SMN 因此，功能不仅在机制上而且在治疗上也相关。其次，虽然很明显 给予 Spinraza 可以为患者带来立竿见影的好处，但现在就做出决定还为时过早 此类治疗的长期结果；该药物被选择性地输送到中枢神经系统，引发了关于 外周慢性低 SMN 的影响。此外，提高SMN的策略在 有症状的患者。在这里，我们描述了 3 组相关的实验，以解决已发现的缺陷 多于。目标 1 提出通过利用新型 SMA 小鼠品系来定义疾病相关机制 早期死亡、运动神经元丧失和严重的表型被延长的生存期、完好无损所取代 运动神经元和明显温和的表型。我们假设伴侣的自发突变 小鼠表达的蛋白质抑制 SMA 表型。我们将确认这一发现并将其扩展至 确定伴侣如何调节低 SMN 的影响。在目标 2 中，我们将研究潜在的长期 表达正常蛋白的模型小鼠肌肉中持续低水平的 SMN 的长期不良影响 中枢神经系统。这些啮齿类动物代表了接受 Spinraza 治疗的 SMA 患者的临床前模型。我们建议 骨骼肌中的慢性低 SMN 对组织的健康产生深远的负面影响 有助于整体 SMA 表型。在目标 3 中，我们将确定低浓度是否会导致疾病 然而，症状后恢复蛋白质后可以减轻肌肉中的 SMN。扭转这样的 缺陷将告诉我们如何修改当前的治疗方法以证明更有效。我们的 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