Evaluation of novel biomarkers of cognition in a model of sporadic developmental brain disorders and their application in efficacy testing of Ras pathway inhibitors

 描述（由申请人提供）：我们的目标是推进智力残疾（ID）和相关疾病（如自闭症谱系障碍和癫痫）小鼠模型的临床前翻译研究的工具和方法。该项目的目标是优化一组预测新兴ID小鼠模型中发育性脑损伤程度的指标，然后使用该指标测试FDA批准的RAS/ERK抑制剂的疗效。诊断性外显子组测序已将SYNGAP 1/Syngap 1鉴定为散发性脑发育障碍患者中最常见的破坏基因之一。我们对这种单基因大脑疾病模型小鼠的研究表明，终身认知障碍是由发育中的前脑神经元的孤立损伤引起的。对这些神经元的损伤会破坏发育的关键期（CP），从而导致终生的认知和行为中断。Syngap 1编码神经元特异性RasGAP，导致单倍不足的致病性突变增强了大脑中的Ras/ERK信号传导。然而，目前尚不清楚前脑海马神经元内RAS/ERK信号传导的升高是否是导致该小鼠模型终身认知障碍的CP损伤的主要原因。基于我们过去的工作，确定了这种遗传形式的ID的核心神经生物学缺陷，我们已经开发了一个明确的和可测试的治疗假设：在新生儿Syngap 1突变体中正常化升高的Ras/ERK信号将保护CP免受损伤，从而减轻持续的认知和行为中断的发展。在ID的小鼠模型中的治疗开发是昂贵的、耗时的，并且产生很少的（如果有的话）转化成功。ID小鼠模型缺乏可翻译性的一个可能原因是缺乏高度可量化的认知功能替代指标。因此，为了最有效地评估Syngap 1模型小鼠中实验疗法的功效，我们还提议验证CP损伤的几种高度可量化的生物标志物。由于这些小鼠的异常认知是由发育CP的损伤引起的，因此这些替代措施有可能对Syngap 1小鼠的认知能力提供高度信息。此外，CP损伤的这些候选生物标志物具有向人类受试者的可转化性的高潜力，因为它们可以在小鼠和人类中容易地获得。重要的是，已知这些潜在的生物标志物中的一些在具有相似Syngap 1功能丧失突变的小鼠和人类患者中给出非常相似的信号。在Syngap 1小鼠中验证高度敏感和可翻译的生物标志物，结合以CP保护为中心的独特治疗假设的有效性测试，表明本提案中概述的工作可以推进用于开发经验疗法的工具和方法。这些进展可以提高从小鼠ID模型转化到相应患者群体的治疗成功率。

 DESCRIPTION (provided by applicant): We aim to advance the tools and methodologies for preclinical translation studies in mouse models of intellectual disability (ID) and related disorders, such as autism spectrum disorder and epilepsy. The goal of this project is to optimize a panel of measures that predict the extent of developmental brain damage in an emerging mouse model of ID and then use this panel to test the efficacy of FDA-approved RAS/ERK inhibitors. Diagnostic exome sequencing has identified SYNGAP1/Syngap1 as one of the most commonly disrupted genes in patients with sporadic brain developmental disorders. Our studies in mice that model this monogenic brain disorder demonstrated that life-long cognitive disruptions are caused by isolated damage to developing forebrain glutamatergic neurons. Damage to these neurons disrupts a critical period (CP) of development that drives life-long cognitive and behavioral disruptions. Syngap1 encodes a neuron-specific RasGAP and pathogenic mutations leading to haploinsufficiency enhance Ras/ERK signaling in the brain. However, it is currently unknown if elevated RAS/ERK signaling within forebrain glutamatergic neurons is the primary cause of CP damage that leads to life-long cognitive disability in this mouse model. Based on our past work that identified the core neurobiological defects that underlie this genetic from of ID, we have developed a clear and testable therapeutic hypothesis: that normalizing elevated Ras/ERK signaling in neonatal Syngap1 mutants will protect the CP from damage and thus mitigate the development of persistent cognitive and behavioral disruptions. Therapeutic development in mouse models of ID is expensive, time consuming and has yielded few, if any, translational successes. One possible reason for the lack of translatability in mouse models of ID is the dearth of highly quantifiable surrogate measures of cognitive function. Thus, in order to most effectively assess the efficacy of experimental therapeutics in Syngap1 model mice, we are also proposing to validate several highly quantifiable biomarkers of CP damage. Because abnormal cognition in these mice is caused by damage to a developmental CP, these surrogate measures have the potential to be highly informative with respect to cognitive ability in Syngap1 mice. In addition, these candidate biomarkers of CP damage have a high potential for translatability to human subjects because they can be acquired easily in both mice and humans. Importantly, some of these potential biomarkers are known to give very similar signals in both mice and humans patients with similar Syngap1 loss-of-function mutations. Validation of highly sensitive and translatable biomarkers in Syngap1 mice, combined with efficacy testing of a unique therapeutic hypothesis centered on CP protection, suggests that the work outlined in this proposal could advance the tools and methodologies used to develop experiential therapeutics. These advances could increase the success rate of therapies translated from mouse ID models to corresponding patient populations.