Therapy for Spinal Muscular Atrophy

脊髓性肌萎缩症的治疗

• 批准号: 8228186
• 负责人: ARTHUR H. M. BURGHES
• 金额: $ 30.65万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-20 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228186
• 关键词: Address; Adult; Affect; Alanine; Alleles; Animals; Aspartic Acid; Automobile Driving; Binding; Biological Assay; CMV promoter; Cells; Disease; Doxycycline; Drug Combinations; Drug Compounding; Drug Delivery Systems; Effectiveness; Elements; Eligibility Determination; Embryo; Excision; Exons; Female; Genetic; Human; In Vitro; Luciferases; Motor Neurons; Mus; Muscular Atrophy; Mutate; Neonatal Screening; Nervous system structure; Neurons; Newborn Infant; Oligonucleotides; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Prions; Proteins; Public Health; Reporting; Research Personnel; Role; SMN1 gene; SMN2 gene; Severities; Siblings; Site; Small Nuclear Ribonucleoproteins; Spinal Muscular Atrophy; System; Tetanus Helper Peptide; Tetracyclines; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenes; cell type; effective therapy; gene therapy; in vivo; infant death; male; mouse model; nestin protein; neurogenetics; neuron loss; overexpression; plastin; promoter; research study; restoration; therapeutic target; treatment strategy

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.

描述(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。近侧SMA是导致婴儿死亡的第二大最常见的遗传原因。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是由于SMN1基因的缺失和SMN2基因的保留，导致野生型SMN水平较低，不足以支持运动神经元的生存。通过增加SMN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确定了可以诱导SMN产生更多SMN蛋白的药物化合物。此外，当药物在运动神经元丧失之前给药时，某些化合物可以改变SMA小鼠的表型。现在已经有可能为SMA进行新生儿筛查。然而，关于SMA中治疗药物的最佳部署仍然存在关键问题，包括激活SMN2的化合物、刺激SMN外显子7被SMN2掺入的寡核苷酸，或者基因治疗。在这项应用中，研究人员将定义高水平SMN的空间和时间要求，以纠正SMA。此外，他们还将研究SMA的修饰剂和联合药物治疗的有效性。为了优化SMA的治疗方案，这些都是必不可少的组成部分。在这一应用中，提出了四个利用SMA小鼠的目标。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条件的小鼠系来确定高水平SMN在神经元或运动神经元以外的组织中的重要性。这将解决在SMA动物中增加神经系统外SMN水平是否有任何好处。2)将使用SMN诱导系统来确定高水平SMN以纠正SMA的时间需求。这将允许确定何时必须在SMA中增加SMN，以及SMN的诱导必须是连续的还是仅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，他们还将确定联合用药是否能提高SMA小鼠的存活率。当前药物的活性必须增加，才能在SMA小鼠中产生重大影响。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的表型。4)最后，报道了SMA表型的修饰物plastin3。研究人员将通过询问增加的plastin3表达是否可以纠正SMA小鼠来确定plastin3是否真的是SMA的修饰物。这里提出的目标将表明SMN诱导的时间和空间要求，确定诱导SMN的最佳化合物组合，并表明已报道的SMA修饰剂在小鼠中的重要性。这将导致SMA治疗方法的优化。 项目简介：脊髓性肌萎缩症(SMA)是导致婴儿死亡的最常见的遗传原因，是由SMN蛋白水平降低引起的。进行新生儿筛查以检测SMA是可能的。该项目的目的是确定在哪里、何时以及如何诱导SMN，以改变SMA的表型，并开发有效的治疗方法。