Developing a novel drug for neurobehavioral deficits in FASD

开发一种治疗 FASD 神经行为缺陷的新药

基本信息

批准号：
10152386
负责人：
Masaaki Torii
金额：
$ 16.47万
依托单位：
COGTHERA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152386
关键词：
Address Affect Angelman Syndrome Attentional deficit Behavior Behavioral Benchmarking Biological Assay Biomedical Research Blood - brain barrier anatomy Body Weight Brain Brain region Capital Cell Survival Child Cognitive Collaborations Computer Models Cultured Cells Custom Defect Development Disease Drug Kinetics Dysmorphology Electrophysiology (science)Excretory function Exhibits Face Fetal Alcohol Spectrum Disorder Functional disorder Funding Goals Healthcare Hospitals Hyperactivity Impaired cognition In Vitro Individual Intervention Investments Joint Ventures Joints Lead Learning Legal patent Metabolism Mission Molecular Mus Neurodevelopmental Disorder Neurologic Neurologic Deficit Neurons Organ Pathologic Patients Peptides Performance Pharmaceutical Preparations Pharmacologic Substance Pharmacological Treatment Phase Phase III Clinical Trials Physiological Placebos Potassium Channel Preclinical Testing Prevalence Property Public Health Research School-Age Population Secure Severities Small Business Technology Transfer Research Specificity Technology Transfer Testing Therapeutic Therapeutic Agents Toxic effect Toxicology Training Treatment Cost United States Validation Variant Western Europe Work absorption alcohol exposure associated symptom base behavior test care burden care costs cytotoxicity design disability drug candidate drug development effective therapy efficacy evaluation efficacy testing endophenotype experimental study field study improved in silico in vivo in vivo evaluation intraperitoneal life time cost malformation motor skill learning mouse model neurobehavioral neurophysiology neuropsychiatric disorder novel novel therapeutics peptide drug phase 1 study phase 2 study preclinical study prenatal exposure reduce symptoms response screening severe intellectual disability side effect

项目摘要

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.

项目概要胎儿酒精谱系障碍 (FASD) 是一种使人衰弱的疾病，会导致多种残疾包括行为和智力缺陷、面部畸形和器官畸形。这种疾病有对医疗保健负担和成本产生深远影响；美国有多达 5% 的儿童受此病影响，每人终生治疗费用高达 200 万美元。尽管事态严重关于这种疾病及其对公共健康的影响，目前尚无可用的治疗方法胎儿酒精谱系障碍。因此，识别可以缓解与相关神经行为问题的治疗分子胎儿酒精谱系障碍 (FASD) 至关重要。我们的长期目标是找到有效的治疗方法来改善认知能力与 FASD 相关的损伤。我们最近发现 KCNN2 钾的靶向使用短肽 Tamapin 的通道可提高小鼠的粗大和精细运动学习技能 FASD 模型。这些发现表明 KCNN2 阻断剂有可能逆转这一趋势与 FASD 和其他神经发育障碍相关的神经行为问题。我们已经使用计算机筛选从 589 个 Tamapin 变体设计中预筛选了 6 个候选肽，以及已经定制合成了它们。 STTR I 期研究的目标是选择主要候选药物证明了在安全改善 FASD 小鼠模型行为缺陷方面的最佳性能。从目前的6名候选人中。我们将重点通过活力/细胞毒性对候选药物进行体外筛选测定和体外电生理学分析（目标 1），并确定先导肽的体内功效改善 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识别来解决与 FASD 相关的神经缺陷的主要公共卫生问题可以缓解这些症状的新型治疗肽。