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 运动神经元存活1（SMN 1）基因突变及其翻译产物SMN水平降低 蛋白质，引起经常致命的，挣扎发作的神经肌肉疾病，脊髓性肌萎缩症（SMA）。 受影响的个体总是携带一个复制基因，SMN 2。然而，SMN 2仅产生残余蛋白质 由于拼接缺陷。尽管如此，考虑到SMA的原因和患者中SMN 2的不变存在，这是 因此，复制基因成为治疗该疾病的最常见靶点也就不足为奇了。的 靶向SMN 2的策略体现在一种FDA批准的药物Spinraza®中，该药物可恢复SMN 通过纠正基因中的剪接缺陷来合成蛋白质。SMN 2的小分子调节剂和 利用病毒载体直接恢复SMN增加了补充蛋白质的治疗剂的选择， 治疗病人。虽然这些发展和SMN的普遍饱和，提高了相当乐观的 SMA的治疗，他们几乎没有做什么来阐明SMN缺乏是如何优先禁用SMA的。 程度的神经肌肉阻滞此外，目前仍不确定是否恢复SMN， 治愈或仅仅延迟疾病的发作。很明显，最有效的结果需要尽早 治疗;有症状的患者获益较少，即使在治疗前， 对症治疗只会将致命疾病转变为慢性疾病。在这里，我们提出的实验， 解决我们对SMA基础生物学理解的差距，作为更好和更有保证的临床研究的一种手段。 结果。因此，在目标1中，我们希望通过利用 在模型小鼠中，菌株特异性差异将严重形式的疾病转变为非常温和的疾病。我们 假设所讨论的基因/因子与我们已经鉴定的伴侣蛋白修饰剂有关， 可能与伴侣蛋白共享功能，这可能意味着SMA中的一种新途径，即突触蛋白稳态。 在目标2中，我们将重点关注原始的伴侣蛋白修饰剂，并设计实验以探索其作为 用于治疗运动神经元疾病的新治疗靶点。我们建议，伴侣，通过其 对蛋白质稳态的影响，增强受影响个体的神经肌肉突触的神经传递 关于SMA最后，在目标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影响肌肉，至少部分地，通过其影响， 常驻祖细胞，破坏这些细胞自我更新的能力，从而损害肌肉修复， 再生如果成功，该项目将a）鉴定SMA表型的新抑制因子，B）揭示SMA表型的新抑制因子， 影响SMA等疾病的不同神经肌肉疾病相关通路，c）解释SMN如何 维持骨骼肌-靶向该组织以最佳治疗人类的基本原理 疾病