Mechanisms and SMN-independent therapies for spinal muscular atrophy

项目摘要 运动神经元1(SMN1)基因存活突变及其翻译产物SMN的低水平表达 蛋白质，会引起经常致命的婴儿发病的神经肌肉疾病，脊髓性肌萎缩症(SMA)。 患有这种疾病的个体总是携带一种复制基因，SMN2。然而，SMN2只产生残留的蛋白质 由于拼接缺陷。尽管如此，考虑到SMA的原因和SMN2在患者中的恒定存在，它是 不足为奇的是，复制基因已经成为治疗这种疾病的最常见的靶点。这个 针对SMN的策略体现在FDA批准的一种药物Spinraza®中，该药物可恢复SMN 通过纠正基因中的剪接缺陷来修复蛋白质。SMN2的小分子调节剂及其治疗 利用病毒载体直接修复SMN增加了补充蛋白质的治疗药物的选择 治疗病人。虽然这些发展和SMN的总体补充，增加了相当乐观的 对于SMA的治疗，他们几乎没有确切地阐明SMN缺乏是如何优先使 神经肌肉系统。此外，是否会恢复目前实行的SMN仍是相当不确定的 治愈或仅仅延缓疾病的发作。已经很明显，最有效的结果需要及早 治疗；有症状的患者获得的好处相当少，即使是在治疗之前 对症治疗只会将一种致命的疾病转变为慢性病。在这里，我们提出了一些实验 解决我们对SMA基本生物学的理解上的差距，作为一种更好和更可靠的临床手段 结果。因此，在目标1中，我们希望通过利用以下方法确定SMA表型的新决定因素 将一种严重的疾病转变为一种非常轻微的疾病的模型鼠之间的菌株特异性差异。我们 假设有问题的基因/因子与我们已经确定的伴侣修饰物有关，因此 可能在SMA中与伴侣分享功能，这可能暗示了一种新的途径-突触蛋白平衡。 在目标2中，我们将重点研究最初的伴侣修饰物，并进行实验，以探索其潜在的 运动神经元病治疗的新靶点。我们建议监护人，通过其 对蛋白稳定的影响，增强患者神经肌肉突触的神经传递 与SMA合作。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。我们假设，低SMN影响肌肉，至少部分是通过它对 驻留的祖细胞，破坏这些细胞的自我更新能力，从而损害肌肉修复和 再生。如果成功，该项目将a)确定一种新的SMA表型抑制因子，b)揭示 影响SMA和c)等疾病的不同神经肌肉疾病相关途径解释SMN 维持骨骼肌--以这种组织为靶点以最佳方式治疗人类的基本原理 疾病。

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.