SMA Biomarkers in the Immediate Post-natal Period of Development

描述（由申请人提供）：在过去两年中，在治疗严重SMA的小鼠模型方面取得了一些突破。在小鼠模型中，增加运动神经元中SMN水平的SMA疗法在出生后的发育阶段最有效，并且它们可以防止虚弱的发展。这些疗法对SMA患者的快速转化受到以下因素的阻碍：1)在该人群中缺乏自然史研究，2)缺乏潜在干预措施生物活性的合格标识符，例如运动神经元中SMN表达的报告，以及3)需要疾病进展和/或疾病改善的合格标记。根据我们进行的临床前实验，我们假设，如果在临床前状态开始治疗，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，以促进婴儿治疗性SMA临床试验的实施：目标1：建立假定的婴儿生理SMA生物标志物的有效性；目的2：在婴儿中建立假定的SMA分子生物标志物的有效性；目的3：建立婴儿运动神经元中SMN水平与假定的SMA生理和分子生物标志物之间的关系。成功实现这些目标将：1)建立SMA患者在最相关发育时期的生理和分子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SMN表达水平与假定的SMA生物标志物之间的相关性；3)识别疾病进展标志物，并确定这些标志物的变化是否预测运动功能下降。

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.