Therapy for Spinal Muscular Atrophy

描述（由申请人提供）：脊髓性肌萎缩症（SMA）的特征是运动神经元的丧失和肌肉的萎缩。近端SMA是婴儿死亡的第二大常见遗传原因。与许多神经遗传疾病一样，突变蛋白SMN普遍表达，但只有一种特定类型的神经元受到影响。SMA是由SMN1基因缺失和SMN2基因保留引起的，导致野生型SMN水平低，不足以维持运动神经元的存活。通过增加SMN2拷贝数来增加SMN水平可以调节表型的严重程度。近年来，研究人员和其他人已经发现了可以诱导SMN2产生更多SMN蛋白的药物化合物。此外，如果在运动神经元丧失之前给药，某些化合物可以改变SMA小鼠的表型。现在对新生儿进行SMA筛查已经成为可能。然而，关键问题仍然是关于SMA治疗的最佳部署，包括激活SMN2的化合物，刺激SMN2结合SMN外显子7的寡核苷酸，或基因治疗。在这个应用程序中，研究人员将定义高水平的SMN来纠正SMA的空间和时间要求。此外，他们将研究SMA的修饰剂和联合药物治疗的有效性。这些都是优化SMA治疗方案的重要组成部分。在这个应用中，使用SMA小鼠提出了四个目的。1)通过使用选择性地在神经元或运动神经元中产生或纠正SMA状况的小鼠系，确定除神经元或运动神经元外组织中高水平SMN的重要性。这将说明增加神经系统外的SMN水平是否对SMA动物有益。2)使用SMN诱导系统来确定对高水平SMN校正SMA的时间要求。这将允许确定在SMA中SMN何时必须增加，以及SMN的诱导是否必须连续或仅在特定的时间窗口内。3)研究磷酸化在SMN纠正SMA能力中的作用。此外，他们将确定药物组合是否能提高SMA小鼠的存活率。当前药物的活性必须增加，才能对SMA小鼠产生重大影响。激活SMN的药物组合，以及SMN磷酸化状态的改变，可能会显著影响SMA表型。4)最后，已经报道了SMA表型的修饰因子plasin3。研究人员将通过询问增加的plasin3表达是否能纠正SMA小鼠，来确定plasin3是否真的是SMA的修饰剂。本文提出的目标将表明SMN诱导的时空要求，确定诱导SMN的最佳化合物组合，并指出已报道的小鼠SMA修饰剂的重要性。这将导致SMA治疗方法的优化。

DESCRIPTION (Provided by Applicant): Spinal muscular atrophy (SMA) is characterized by loss of motor neurons and atrophy of muscle. Proximal SMA is the second most common genetic cause of infant death. As in many neurogenetic disorders, the mutated protein SMN is ubiquitously expressed, yet only a particular type of neuron is affected. SMA is caused by loss of the SMN1 gene and retention of the SMN2 gene, leading to low levels of wild-type SMN, which is insufficient for motor neuron survival. Increasing SMN levels by increasing SMN2 copy number modulates the severity of the phenotype. In recent years the investigators, and others, have identified drug compounds that can induce SMN2 to produce more SMN protein. In addition, when the drug is given prior to motor neuron loss certain compounds can modify the SMA mouse phenotype. It has now become possible to perform newborn screening for SMA. However key questions remain concerning optimal deployment of therapeutics in SMA, including compounds that activate SMN2, oligonucleotides that stimulate incorporation of SMN exon7 by SMN2, or gene therapy. In this application the investigators will define the spatial and temporal requirement for high levels of SMN to correct SMA. Additionally, they will study modifiers of SMA and the effectiveness of combination drug treatments. These are essential components in order to optimize treatment regimes for SMA. In this application four aims are proposed using SMA mice. 1) Determine the importance of high levels of SMN in tissues other than neurons or motor neurons by using mouse lines that selectively create or correct the SMA condition in neurons or motor neurons. This will address if there is any benefit in SMA animals of increasing SMN levels outside the nervous system. 2) The temporal requirement for high levels of SMN to correct SMA will be determined using a SMN inducible system. This will allow determination of when SMN must be increased in SMA and whether induction of SMN must be continuous or just during a specific window of time. 3) Study the role of phosphorylation in SMN's ability to correct SMA. Additionally, they will determine if combinations of drug increase survival in SMA mice. The activity of current drugs must be increased in order to have a major impact in the SMA mouse. Combinations of drugs that activate SMN, as well as alteration of the phosphorylation state of SMN, may significantly impact the SMA phenotype. 4) Lastly, a modifier of the SMA phenotype, plastin3, has been reported. The investigators will determine if plastin3 is truly a modifier of SMA by asking whether increased plastin3 expression can correct SMA mice. The aims proposed here will indicate the temporal spatial requirement for SMN induction, identify the optimal compound combination for induction of SMN, and indicate the importance of a reported modifier of SMA in mice. This will result in optimization of therapeutics for SMA. PROJECT NARRATIVE: Spinal muscular atrophy (SMA) is the most common genetic cause of infant death and is caused by reduced levels of the SMN protein. It is possible to perform neonatal screens to detect SMA. The aim of this project is to determine where, when, and how to induce SMN so as to modify the SMA phenotype and develop effective treatment for SMA.