Therapy for Spinal Muscular Atrophy

脊髓性肌萎缩症的治疗

基本信息

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
项目类别：
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

项目摘要

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）的特征是运动神经元丧失和肌肉萎缩。近端 SMA 是婴儿死亡的第二常见遗传原因。与许多神经遗传性疾病一样，突变蛋白 SMN 普遍表达，但只有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 水平低下，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，从而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 SMN2 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 小鼠的表型。现在可以对新生儿进行 SMA 筛查。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 掺入 SMN 外显子 7 的寡核苷酸或基因治疗。在此应用中，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。这些是优化 SMA 治疗方案的重要组成部分。在此应用中，使用 SMA 小鼠提出了四个目标。 1) 通过使用选择性地在神经元或运动神经元中创建或纠正 SMA 状况的小鼠品系，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。这将解决增加神经系统外 SMN 水平是否对 SMA 动物有任何好处。 2) 将使用 SMN 诱导系统确定高水平 SMN 纠正 SMA 的时间要求。这将允许确定何时必须在 SMA 中增加 SMN，以及 SMN 的诱导是否必须连续或仅在特定时间窗口内进行。 3）研究磷酸化在SMN纠正SMA能力中的作用。此外，他们还将确定药物组合是否可以提高 SMA 小鼠的存活率。必须提高现有药物的活性才能对 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着影响 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增加plastin3表达是否可以纠正小鼠的SMA来确定plastin3是否真正是SMA的修饰剂。这里提出的目标将表明 SMN 诱导的时间空间要求，确定诱导 SMN 的最佳化合物组合，并表明已报道的小鼠 SMA 修饰剂的重要性。这将优化 SMA 的治疗方法。项目叙述：脊髓性肌萎缩症 (SMA) 是婴儿死亡最常见的遗传原因，是由 SMN 蛋白水平降低引起的。可以进行新生儿筛查来检测 SMA。该项目的目的是确定何时、何地以及如何诱导 SMN，从而改变 SMA 表型并开发 SMA 的有效治疗方法。