Mechanisms and SMN-independent therapies for spinal muscular atrophy

脊髓性肌萎缩症的机制和不依赖 SMN 的疗法

• 批准号: 10435837
• 负责人: Umrao Monani
• 金额: $ 57.66万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10435837
• 关键词: 2 year old; Address; Adopted; Affect; Age; Alzheimer' s Disease; Animal Model; Antisense Oligonucleotides; Area; Biology; Cell physiology; Cells; Characteristics; Childhood; Chronic; Clinical; Data; Defect; Development; Disease; Early treatment; Encapsulated; FDA approved; Genes; Genetic; Genetic study; Genome; Goals; Growth; Housekeeping; Human; Impairment; Individual; Intervention; Intuition; Left; Length; Light; Maintenance; Molecular Chaperones; Motor Neuron Disease; Motor Neurons; Mouse Strains; Mus; Muscle; Muscle Cells; Muscle Development; Muscular Atrophy; Mutation; Natural regeneration; Neurodegenerative Disorders; Neuromuscular Diseases; Onset of illness; Outcome; Paralysed; Pathology; Pathway interactions; Patients; Phenotype; Proteins; RNA Splicing; Reporting; Research; Residual state; Respiratory distress; SMN protein (spinal muscular atrophy); SMN1 gene; SMN2 gene; Severities; Signal Transduction; Skeletal Muscle; Spinal; Spinal Muscular Atrophy; Synapses; Testing; Therapeutic; Therapeutic Agents; Tissues; Transcript; Translating; Variant; Viral Vector; Work; adeno-associated viral vector; clinically relevant; design; disease phenotype; experimental study; gene replacement; genetic linkage analysis; genetic strain; human disease; improved; infancy; mouse model; neuromuscular; neuromuscular system; neuron loss; neurotransmission; new therapeutic target; notch protein; novel; optimism; pre-clinical; prevent; progenitor; proteostasis; repaired; satellite cell; self-renewal; small molecule; stem; stem cells; success; symptom treatment; therapeutic evaluation

Project Summary Mutations in the Survival of Motor Neuron 1 (SMN1) gene and low levels of its translated product, the SMN protein, provoke the frequently fatal, infantile-onset neuromuscular disorder, spinal muscular atrophy (SMA). Afflicted individuals invariably carry a copy gene, SMN2. However, SMN2 produces only residual protein owing to a splicing defect. Still, given the cause of SMA and the invariable presence of SMN2 in patients, it is not surprising that the copy gene has served as the most common target for the treatment of the disease. The strategy of targeting SMN2 is embodied in one FDA-approved agent, Spinraza®, which restores the SMN protein by correcting the splicing defect in the gene. Small molecule modulators of SMN2 and therapies that exploit viral vectors to directly restore SMN add to the choice of therapeutic agents that replenish the protein to treat patients. While these developments and SMN repletion in general, raise considerable optimism for the treatment of SMA, they have done little to shed light on precisely how SMN paucity preferentially disables the neuromuscular system. Besides, it is still quite uncertain if restoring SMN as currently practiced will be curative or merely delay the onset of disease. Already it is clear that the most effective outcomes require early treatment; symptomatic patients derive considerably less benefit, and it would not be surprising if even pre- symptomatic treatment merely converts a fatal disease into a chronic one. Here we propose experiments that address gaps in our understanding of the basic biology of SMA as a means to better and more assured clinical outcomes. Accordingly, in Aim 1, we wish to identify a novel determinant of the SMA phenotype by exploiting strain-specific differences in model mice that turn a severe form of the disease into a remarkably mild one. We hypothesize that the gene/factor in question is related to a chaperone modifier we have identified and thus likely shares functions with the chaperone in what could imply a novel pathway, synaptic proteostasis, in SMA. In Aim 2, we will focus on the original chaperone modifier with experiments designed to explore its potential as a novel therapeutic target for the treatment of motor neuron disease. We propose that the chaperone, via its effects on proteostasis, potentiates neurotransmission at the neuromuscular synapses of individuals afflicted with SMA. Finally, in Aim 3, we will investigate how reduced SMN in skeletal muscle contributes to the neuromuscular SMA phenotype. We posit that low SMN affects muscle, at least in part, through its effects on resident progenitor cells, disrupting the ability of these cells to self-renew and thus impairing muscle repair and regeneration. If successful, the project will a) identify a novel suppressor of the SMA phenotype, b) reveal a distinct neuromuscular disease-relevant pathway that impacts disorders like SMA and, c) explain how SMN maintains skeletal muscle – the underlying rationale for targeting this tissue to optimally treat the human disease.

项目摘要 运动神经元1（SMN1）基因的生存中的突变及其翻译产物的低水平SMN 蛋白质会引起经常致命的，婴儿发作的神经肌肉疾病，脊柱肌肉萎缩（SMA）。 受苦的个体总是携带复制基因SMN2。但是，SMN2仅产生残留蛋白 由于剪接缺陷。尽管如此，鉴于SMA的原因和患者中SMN2的不变，这是 毫不奇怪，复制基因已成为治疗该疾病的最常见靶标。 靶向SMN2的策略体现在一个FDA批准的代理SpinRaza®中，该代理恢复了SMN 蛋白质通过校正基因中的剪接缺陷。 SMN2和疗法的小分子调节剂 利用病毒载体直接恢复SMN，增加了复制蛋白质的治疗剂的选择 治疗患者。尽管这些发展和SMN的复制总体上，但对 对SMA的处理，他们几乎没有阐明SMN的贫困如何优先删除 神经肌肉系统。此外，目前练习是否还会恢复SMN，仍然不确定是否会 治愈或仅延迟疾病的发作。已经很明显最有效的结果需要及早 治疗;有症状的患者谨慎地获得较少的好处，即使是 有症状的治疗仅将致命疾病转化为慢性疾病。在这里，我们提出了实验 解决我们对SMA基本生物学的理解中的差距，作为更好，更假设临床的手段 结果。根据AIM 1的说法，我们希望通过利用SMA表型的新颖决定者 模型小鼠的菌株特异性差异将严重的疾病形式变成一种非常温和的差异。我们 假设所讨论的基因/因素与我们已经鉴定的伴侣修饰符有关，从而 在SMA中，可能与伴侣的功能与伴侣的功能可能暗示着一种新型的途径，即突触蛋白质的。 在AIM 2中，我们将通过旨在探索其潜力的实验专注于原始的链条修饰符 一种用于治疗运动神经元疾病的新型热靶标。我们建议伴侣通过其 对蛋白质的影响，潜在的人在受折磨的个体的神经肌肉突触上神经传递 与SMA。最后，在AIM 3中，我们将研究骨骼肌中SMN的减少如何有助于 神经肌肉SMA表型。我们认为低SMN至少部分地影响了肌肉。 居民祖细胞，破坏了这些细胞自我更新的能力，从而损害了肌肉修复和 再生。如果成功，该项目将a）识别SMA表型的新型抑制剂，b）揭示 不同的神经肌肉疾病与疾病相关的途径影响SMA等疾病，C）解释SMN如何 保持骨骼肌 - 针对该组织以最佳治疗人类的基本原理 疾病。