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（由申请方提供）：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）的缺失或突变导致人类SMA疾病。人类基因组包含一个几乎相同的基因SMN2，它与SMN1在功能上是冗余的。然而，由于外显子7中的剪接突变，SMN2基因的表达严重受损。SMA患者的疾病严重程度与SMN 2拷贝数呈负相关，最低水平的SMN蛋白导致最严重的SMA表型。虽然严重形式的SMA是致命的，但中度和轻度形式的疾病会导致患者不动和呼吸问题。重度SMA小鼠模型中SMN蛋白的恢复已显示部分挽救了疾病表型，但尚未对中度或轻度SMA模型中神经功能缺损的恢复进行治疗试验。因此，迫切需要开发中间SMA小鼠模型并确定中间至轻度形式的疾病的治疗窗口。在缺乏这些知识的情况下，充分的治疗将仍然难以实现，SMA将继续成为残疾和死亡的主要原因。该申请的主要重点是利用小鼠模型研究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（接近SMA IV型），小鼠基因Smn突变产生低水平的SMN蛋白。此外，为了产生急需的中间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（使用阴性ASO靶向剪接以模拟疾病）进一步降低我们当前轻度模型中的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。