Testing Therapies in a New Mild SMA Mouse: A Model for Type II/III Patients

在新型轻度 SMA 小鼠中测试疗法：II/III 型患者模型

• 批准号: 8444878
• 负责人: Cathleen M Lutz
• 金额: $ 26.25万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444878
• 关键词: A Mouse; Address; Affect; Age; Alleles; Animals; Antisense Oligonucleotides; Body Weight; Breeding; Clinic; Clinical; Conduct Clinical Trials; Development; Disease; Disease Progression; Disease model; Drug Delivery Systems; Early treatment; Engineering; Genes; Genetic; Individual; Infant; Intervention; Knock-out; Laboratory Research; Longevity; Manuscripts; Measurable; Measures; Modeling; Monitor; Morphology; Motor Neurons; Mus; Neurodegenerative Disorders; Neuromuscular Junction; Onset of illness; Patients; Pharmacotherapy; Phenotype; Preclinical Testing; Production; SMN protein (spinal muscular atrophy); SMN2 gene; Severity of illness; Spinal Muscular Atrophy; System; Tamoxifen; Testing; Therapeutic; Therapeutic Effect; Time; Toddler; Treatment outcome; Up-Regulation; Validation; Weaning; Weight; Work; design; effective therapy; mouse model; muscle strength; neuromuscular; postnatal; pre-clinical; protein expression; research study; restoration; small molecule; tool; treatment strategy

DESCRIPTION (provided by applicant): Several promising therapeutic strategies for the treatment of Spinal Muscular Atrophy (SMA) are currently being pursued. As these therapies start to move from the research laboratory to the clinic, it becomes imperative to understand how effective these therapies will be after the onset of disease and if there is a critical window for drug delivery. To address this question of timing in delivering therapies, we have designed a study to evaluate the efficacy of increasing survival motor neuron (SMN) levels throughout development using a new preclinical SMA mouse model, called the Burgheron mouse. In this proposal we describe the Burgheron model, which we generated by breeding a combination of alleles to achieve mice that have intermediate SMN2 levels. Previous attempts to engineer mild SMA models have been relatively unsuccessful, resulting in mice with near normal life spans and little to no measurable phenotype. The Burgheron mice have a noted decrease in body weight, a mean lifespan of 54 days of age and quantifiable abnormalities at the neuromuscular junction, and measure differences in muscle strength. This increased lifespan presents a clear advantage over the currently used severe models of SMA that die early at 17 days of age in that it allows us to begin testing the effects of increasing SMN at later postnatal time points, even well past weaning. By incorporating a conditional inversion allele at the Smn1 locus we can transform the Burgheron model described above into an inducible system that activates SMN production via tamoxifen induction. This allows us to better characterize the effects of introducing SMN into a disease model at various time points in disease progression. In addition, we have chosen a number of different candidate therapeutics to serve the purpose of tool compounds to explore the question of a therapeutic window for treatment.

描述（由申请人提供）：目前正在追求几种有前途的治疗脊柱肌肉萎缩（SMA）的有前途的治疗策略。随着这些疗法开始从研究实验室转移到诊所，必须了解这些疗法在疾病发作后将有多么有效，以及是否有关键的药物输送窗口。为了解决交付疗法的时间问题，我们设计了一项研究，以评估使用新的临床前SMA小鼠模型（称为Burgheron小鼠）在整个发育过程中提高生存运动神经元（SMN）水平的功效。在此提案中，我们描述了汉堡模型，我们通过繁殖等位基因的组合来实现具有中间SMN2水平的小鼠而产生的。以前试图设计温和的SMA模型的尝试相对不成功，导致小鼠的寿命接近正常，几乎没有可测量的表型。汉堡小鼠的体重降低，平均寿命为54天，在神经肌肉结处的平均寿命和可量化的异常，并测量肌肉力量的差异。这种增加的寿命比当前使用的严重SMA模型具有明显的优势，该模型在17天大时就死亡，这使我们能够开始测试出生后时间点增加SMN的效果，甚至在断奶之前。通过在SMN1基因座上合并有条件的反转等位基因，我们可以将上述汉语模型转换为可诱导的系统，该系统通过他莫昔芬诱导激活SMN产生。这使我们能够更好地表征将SMN在疾病进展的不同时间点引入疾病模型的影响。此外，我们选择了许多不同的候选治疗剂来实现工具化合物的目的，以探索治疗窗口的问题。