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

• 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
• 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

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.

项目摘要 胎儿酒精谱系障碍（FASD）是一种导致广泛残疾的衰弱性疾病 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;美国境内多达5%的儿童 受这种疾病影响的人，每人一生的治疗费用达到200万美元。尽管严重 这种疾病及其对公共卫生的影响，目前还没有治疗方法可用于 FASD。因此，鉴定可以减轻与神经行为相关的神经行为问题的治疗分子， FASD非常关键。我们的长期目标是找到有效的治疗方法来改善认知障碍， 与FASD相关的损伤。我们最近发现KCNN 2钾的靶向作用 通道使用短肽Tamapin，改善了我们小鼠的粗运动和精细运动学习技能 FASD模型。这些发现表明，KCNN 2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 使用计算机筛选从589种Tamapin变体设计中预筛选6种肽候选物，和 定制合成的本STTR I期研究的目标是选择先导候选药物 这证明了在安全地改善FASD小鼠模型中的行为缺陷方面的最佳性能。 目前的6名候选人。我们将专注于通过活力/细胞毒性对候选人进行体外筛选 测定和体外电生理学分析（目的1），并定义前导肽的体内功效， 改善FASD小鼠模型神经行为缺陷（目的2）。这项研究具有巨大的潜力， 通过识别与FASD相关的神经功能缺损这一重大公共卫生问题， 可以减轻这些症状的新型治疗肽。