Developing a novel drug for neurobehavioral deficits in FASD

项目摘要 胎儿酒精光谱障碍(FASD)是一种导致多种残疾的衰弱疾病 包括行为和智力缺陷、面部畸形和器官畸形。这一障碍有 对医疗负担和成本产生深远影响；美国多达5%的儿童 受这种情况影响，终身治疗费用达到每人200万美元。尽管情况很严重 关于这种疾病及其对公共健康的影响，目前还没有治疗方法 FASD。因此，确定治疗分子可以缓解与以下疾病相关的神经行为问题 FASD是至关重要的。我们的长期目标是寻找有效的治疗方法来改善认知能力。 与FASD相关的损害。我们最近发现，KCNN_2钾的靶向 使用短肽Tamapin的通道可以改善小鼠的粗大和精细运动学习技能 FASD的模型。这些发现表明，KCNN2阻滞剂有可能逆转 与FASD和其他神经发育障碍相关的神经行为问题。我们已经这么做了 从用于电子筛查的589个Tamapin变异体设计中预筛选6个候选多肽，以及 已经定制合成了它们。这项STTRI期研究的目标是选择主要候选药物(S) 这表明在安全改善FASD小鼠模型的行为缺陷方面表现最好。 从目前的6名候选人中选出。我们将专注于通过活性/细胞毒性进行候选人的体外筛选 分析和体外电生理分析(目标1)，并确定铅多肽的体内疗效 改善FASD小鼠模型的神经行为缺陷(目标2)。这项研究在以下方面具有巨大潜力 通过确定与FASD相关的神经缺陷来解决重大公共卫生问题 可能缓解这些症状的新型治疗性多肽。

Project Summary Fetal Alcohol Spectrum Disorder (FASD) is a debilitating condition causing a wide range of disabilities including behavioral and intellectual deficits, facial dysmorphology, and organ malformations. This disorder has a profound impact on health care burden and cost; as many as 5% of children within the United States are affected by this condition, with lifetime treatment costs reaching $2 million per individual. Despite the severity of this disorder and its impact on public health, there currently are no therapeutic treatments available for FASD. As such, identifying therapeutic molecules that can alleviate neurobehavioral issues associated with FASD is critical. Our long-term objective is to identify effective treatments to ameliorate the cognitive impairments associated with FASD. We have recently discovered that the targeting of the KCNN2 potassium channel using a short peptide, Tamapin, improves both the gross and fine motor learning skills in our mouse model of FASD. These findings suggest that KCNN2 blockers have the potential to reverse the neurobehavioral problems associated with FASD and other neurodevelopmental disorders. We have already prescreened 6 peptide candidates from the 589 designs of Tamapin variants using in silico screening, and have custom-synthesized them. The goal of this STTR Phase I study is to select the lead drug candidate(s) that demonstrate the best performance in safely improving behavioral deficits in the mouse model of FASD. from the current 6 candidates. We will focus on in vitro screening of candidates through viability/cytotoxicity assays and in vitro electrophysiology analysis (Aim 1), and defining the in vivo efficacy of the lead peptides to improve neurobehavioral deficits in a mouse model of FASD (Aim 2). This research has immense potential in addressing the major public health issue of neurological deficits associated with FASD through identifying novel therapeutic peptides that may alleviate these symptoms.