Using TSUNAMI in a sensitized mouse to generate an intermediate SMA model

在致敏小鼠中使用 TSUNAMI 生成中间 SMA 模型

• 批准号: 8772680
• 负责人: Dawn S Chandler
• 金额: $ 21.98万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772680
• 关键词: Address; Attenuated; Birth; Cessation of life; Defect; Degenerative Disorder; Development; Disease; Enhancers; Exhibits; Exons; Genes; Genetic; Goals; Human; Human Genome; Incidence; Infant Mortality; Knock-in Mouse; Knowledge; Length; Life; Life Expectancy; Methodology; Methods; Modeling; Motor; Motor Neurons; Mus; Muscle Weakness; Mutate; Mutation; Neurologic; Onset of illness; Patients; Phenotype; Proteins; Publishing; RNA Splicing; Research; Resources; Respiratory distress; SMN protein (spinal muscular atrophy); SMN2 gene; Severities; Severity of illness; Spinal Muscular Atrophy; Symptoms; System; Tamoxifen; Techniques; Technology; Testing; Therapeutic; Therapeutic Human Experimentation; Therapeutic Studies; Time; Transcript; Underserved Population; United States; disability; disease phenotype; disorder prevention; effective therapy; gene replacement; improved; meetings; mouse model; muscle strength; novel; patient population; public health relevance; recombinase; respiratory; restoration; survival motor neuron gene

DESCRIPTION (provided by applicant): Proximal spinal muscular atrophy (SMA) is a neuro-degenerative disease that is a primary genetic cause of infant mortality. Deletion or mutation of the survival motor neuron-1 (SMN1) gene leads to the SMA disease in humans. The human genome harbors a nearly identical gene, SMN2, that is functionally redundant with SMN1. However, expression of the SMN2 gene is severely compromised as a result of a splicing mutation in exon 7. Disease severity in SMA patients is inversely correlated with the copy number of SMN2 with the lowest levels of SMN protein causing the most severe SMA phenotypes. While the severe forms of SMA are fatal, the intermediate and mild forms of the disease cause immobility and respiratory issues for patients. Restoration of SMN protein to severe SMA mouse models has shown partial rescue of the disease phenotype, however there has been no therapeutic testing for restoration of neurological defects in intermediate or mild models for SMA. Therefore, there is a critical need to develop an intermediate SMA mouse model and to determine the therapeutic window for the intermediate to mild forms of the disease. In the absence of such knowledge, adequate treatment will remain elusive and SMA will continue to be a leading cause of disability and death. The main focus of this application is to utilize mouse models to study the treatment of SMA, with the long-term goal of testing candidate therapies to correct the neuro-degenerative defect in patients. To this end, our lab has developed a new mild SMA mouse model (approximates SMA TYPE IV) with the mouse gene, Smn, mutated to produce low levels of the SMN protein. Furthermore, in order to generate the much needed intermediate SMA mouse model (similar to Type III in humans), we hypothesize that we will be able to further decrease the levels of SMN protein in our current mild model by using the recently published TSUNAMI technique (targeting splicing using negative ASOs to model illness). We aim to determine the therapeutic window for the intermediate model that we generate.

描述（由申请人提供）：近端脊髓性肌萎缩症（SMA）是一种神经退行性疾病，是婴儿死亡的主要遗传原因。运动神经元存活基因 1 (SMN1) 基因的缺失或突变会导致人类 SMA 疾病。人类基因组包含一个几乎相同的基因 SMN2，它在功能上与 SMN1 冗余。然而，由于外显子7的剪接突变，SMN2基因的表达受到严重损害。SMA患者的疾病严重程度与SMN2的拷贝数呈负相关，最低水平的SMN蛋白导致最严重的SMA表型。虽然严重的 SMA 是致命的，但中度和轻度的 SMA 会导致患者行动不便和出现呼吸问题。对严重 SMA 小鼠模型恢复 SMN 蛋白已显示出部分挽救了疾病表型，但尚未对中度或轻度 SMA 模型中的神经缺陷恢复进行治疗测试。因此，迫切需要开发中度 SMA 小鼠模型并确定中度至轻度疾病的治疗窗口。如果缺乏这些知识，充分的治疗仍然难以实现，SMA 将继续成为残疾和死亡的主要原因。该应用的主要重点是利用小鼠模型来研究 SMA 的治疗，长期目标是测试候选疗法以纠正患者的神经退行性缺陷。为此，我们的实验室开发了一种新的轻度 SMA 小鼠模型（近似 SMA IV 型），其小鼠基因 Smn 发生突变，产生低水平的 SMN 蛋白。此外，为了生成急需的中间 SMA 小鼠模型（类似于人类 III 型），我们假设我们将能够通过使用最近发表的 TSUNAMI 技术（使用负 ASO 进行靶向剪接来模拟疾病）来进一步降低当前轻度模型中的 SMN 蛋白水平。我们的目标是确定我们生成的中间模型的治疗窗口。