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（由申请人提供）：在过去两年中，在治疗严重SMA的小鼠模型时已经取得了许多突破。在产后发育的直接发育期间，SMA疗法提高运动神经元的SMN水平是最有效的，并且可以防止小鼠模型中的弱点发展。这些疗法向SMA患者的快速翻译受到包括：1）在该人群中的自然历史研究的因素的阻碍，2）缺乏潜在干预措施的生物学活性的合格识别剂，例如运动神经元中SMN表达的记者，以及3）需要对疾病进展和/或疾病的疾病的合格标记。根据我们进行的临床前实验，我们假设SMA临床试验如果以临床前状态开始治疗，那么SMA临床试验的成功可能性很高。因此，我们提出了以下具体目标，以识别疾病进展的预后生物标志物和替代生物标志物，这将促进婴儿的治疗性SMA临床试验的执行：目标1：确定婴儿假定生理SMA生物标志物的有效性；目标2：确定婴儿推定的分子SMA生物标志物的有效性； AIM 3：建立运动神经元中SMN水平与婴儿中假定的生理和分子SMA生物标志物之间的关系。这些目标的成功追求将：1）在最相关的发育时期确定SMA患者的生理和分子SMA生物标志物的自然史，2）在运动神经元中使用大型动物模型和3）确定疾病进展的标记并确定这些标记的变化是否预测这些标记的运动能力降低。 公共卫生相关性：脊柱肌肉萎缩是婴儿的主要遗传杀手。有力的临床前证明，必须尽早提供有效的SMA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，这将促进婴儿的治疗性SMA临床试验。