Therapy for Spinal Muscular Atrophy

脊髓性肌萎缩症的治疗

• 批准号: 8048166
• 负责人: ARTHUR H. M. BURGHES
• 金额: $ 30.95万
• 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/8048166
• 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（由申请人提供）：脊髓性肌萎缩症（SMA）的特征在于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。 与许多神经遗传性疾病一样，突变蛋白SMN广泛表达，但只有特定类型的神经元受到影响。 SMA是由SMN1基因的丢失和SMN2基因的保留引起的，导致低水平的野生型SMN，这不足以维持运动神经元的存活。 通过增加SMN2拷贝数增加SMN水平可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 2产生更多SMN蛋白的药物化合物。 此外，当在运动神经元丧失之前给予药物时，某些化合物可以改变SMA小鼠表型。 现在可以进行新生儿SMA筛查。 然而，关于SMA治疗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通过SMN2掺入的寡核苷酸或基因治疗。 在本申请中，研究者将定义高水平SMN矫正SMA的空间和时间要求。 此外，他们还将研究SMA的修饰剂和联合药物治疗的有效性。 这些是优化SMA治疗方案的重要组成部分。 在本申请中，提出了使用SMA小鼠的四个目的。 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，确定神经元或运动神经元以外的组织中高水平SMN的重要性。 这将解决SMA动物在神经系统外增加SMN水平是否有任何益处。 2)将使用SMN诱导系统确定高水平SMN纠正SMA的时间要求。 这将允许确定SMA中何时必须增加SMN，以及SMN的诱导是否必须是连续的或仅在特定时间窗内。 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会增加SMA小鼠的存活率。 为了在SMA小鼠中产生重大影响，必须增加当前药物的活性。 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，SMA表型的修饰剂，plastin3，已被报道。 研究人员将通过询问plastin3表达增加是否可以纠正SMA小鼠来确定plastin3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，并表明小鼠中SMA修饰剂的重要性。 这将导致SMA治疗的优化。 项目叙述：脊髓性肌萎缩症（SMA）是婴儿死亡的最常见遗传原因，由SMN蛋白水平降低引起。 可以进行新生儿筛查以检测SMA。 本项目的目的是确定在何处、何时以及如何诱导SMN，以改变SMA表型并开发有效的SMA治疗方法。