SMA Biomarkers in the Immediate Post-natal Period of Development

产后发育初期的 SMA 生物标志物

• 批准号: 8327493
• 负责人: Stephen J. Kolb
• 金额: $ 82.35万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327493
• 关键词: 2 year old; Action Potentials; Address; Affect; Age; Animal Model; Biological; Biological Markers; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Data; Development; Disease; Disease Marker; Disease Progression; Family suidae; Gene Dosage; Genetic; Human; Human Development; Infant; Intervention; Life; Live Birth; Measurement; Measures; Messenger RNA; Modeling; Molecular; Motor; Motor Neurons; Mus; Muscle; Myography; Natural History; Patients; Physiological; Population; Predictive Value; Proteins; Qualifying; Reporter; Reporting; Respiratory Failure; SMN1 gene; SMN2 gene; Severity of illness; Spinal; Spinal Cord; Spinal Muscular Atrophy; Staging; Therapeutic; Therapeutic Intervention; Time; Translations; Visit; base; cell type; cellular targeting; cohort; effective therapy; electric impedance; infant death; laser capture microdissection; mRNA Expression; mouse model; nerve supply; optimism; patient population; postnatal; pre-clinical; preclinical study; prevent; prognostic; protein expression; research study; response; small hairpin RNA; success

DESCRIPTION (provided by applicant): There have been a number of breakthroughs in the treatment of a mouse model of severe SMA in the last two years. SMA therapies that increase SMN levels in motor neurons have been most effective when delivered in the immediate postnatal period of development and they prevent the development of weakness in the mouse model. The rapid translation of these therapies to SMA patients is hampered by factors that include: 1) the paucity of natural history studies in this population, 2) the absence of qualified identifiers of biological activity of potential interventions, for example a reporter of the expression of SMN in motor neurons, and 3) the need for qualified markers of disease progression and/or markers of disease amelioration. We hypothesize, based on preclinical experiments that we have performed, that SMA clinical trials have the highest likelihood of success if therapy is initiated in a pre-clinical state. We thus propose the following specific aim in identify prognostic biomarkers and surrogate biomarkers of disease progression that will facilitate the execution of therapeutic SMA clinical trials in infants: Aim 1: To establish the validity of putative physiological SMA biomarkers in infants; Aim 2: To establish the validity of putative molecular SMA biomarkers in infants; Aim 3: To establish the relationship between SMN levels in motor neurons with putative physiological and molecular SMA biomarkers in infants. The successful pursuit these Aims will: 1) establish the natural history of physiological and molecular SMA biomarkers in SMA patients at the most relevant period of development, 2) establish a correlation between SMN expression levels in motor neurons with putative SMA biomarkers using a large animal model, and 3) identify markers of disease progression and determine whether changes in these markers predict motor function decline. PUBLIC HEALTH RELEVANCE: Spinal muscular atrophy is the leading genetic killer of infants. Strong preclinical evidence suggests that effective therapy in SMA must be delivered as early as possible to prevent progression of the disease. This project will identify prognostic biomarkers and surrogate biomarkers of disease progression that will facilitate the execution of therapeutic SMA clinical trials in infants.

描述（申请人提供）：过去两年，严重 SMA 小鼠模型的治疗取得了多项突破。增加运动神经元 SMN 水平的 SMA 疗法在出生后发育时期最有效，并且可以防止小鼠模型出现无力。这些疗法在 SMA 患者中的快速转化受到以下因素的阻碍：1）该人群中缺乏自然史研究，2）缺乏潜在干预措施的生物活性的合格标识符，例如运动神经元中 SMN 表达的报告器，以及 3）需要疾病进展的合格标志物和/或疾病改善的标志物。根据我们进行的临床前实验，我们假设，如果在临床前状态下开始治疗，SMA 临床试验成功的可能性最高。因此，我们提出以下具体目标，以确定疾病进展的预后生物标志物和替代生物标志物，这将有助于在婴儿中执行治疗性 SMA 临床试验： 目标 1：确定婴儿中假定的生理 SMA 生物标志物的有效性；目标 2：确定婴儿 SMA 分子生物标志物的推定有效性；目标 3：建立婴儿运动神经元中 SMN 水平与假定的生理和分子 SMA 生物标志物之间的关系。成功实现这些目标将：1）在最相关的发育时期建立 SMA 患者的生理和分子 SMA 生物标志物的自然史，2）使用大型动物模型建立运动神经元中的 SMN 表达水平与假定的 SMA 生物标志物之间的相关性，以及 3）识别疾病进展的标志物并确定这些标志物的变化是否预测运动功能下降。 公共卫生相关性：脊髓性肌萎缩症是婴儿的主要遗传杀手。强有力的临床前证据表明，必须尽早对 SMA 进行有效治疗，以防止疾病进展。该项目将确定疾病进展的预后生物标志物和替代生物标志物，这将有助于在婴儿中执行治疗性 SMA 临床试验。