SMA Biomarkers in the Immediate Post-natal Period of Development

描述（由申请人提供）：在过去两年中，重度SMA小鼠模型的治疗取得了许多突破。增加运动神经元中SMN水平的SMA疗法在出生后立即发育期间递送时最有效，并且它们防止小鼠模型中虚弱的发展。这些治疗在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）缺乏潜在干预措施生物活性的合格标识符，例如运动神经元中SMN表达的报告基因，3）需要合格的疾病进展标志物和/或疾病改善标志物。根据我们已经进行的临床前实验，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，我们提出了以下具体目标，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进行治疗性SMA临床试验：目标1：确定婴儿中推定的生理SMA生物标志物的有效性;目标2：确定婴儿中推定的分子SMA生物标志物的有效性;目标3：确定婴儿运动神经元中SMN水平与假定的生理和分子SMA生物标志物之间的关系。这些目标的成功实现将：1）在最相关的发育期建立SMA患者生理和分子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表达水平与推定SMA生物标志物之间的相关性，3）鉴定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，SMA的有效治疗必须尽早进行，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进行治疗性SMA临床试验。

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.