Preparing for a Clinical Trial in Kabuki Syndrome- Characterization of Cognitive and Neuroanatomical Features and Pilot Treatment Trial

准备歌舞伎综合症的临床试验——认知和神经解剖学特征的表征和试点治疗试验

• 批准号: 10220096
• 负责人: Jacqueline Harris
• 金额: $ 16.87万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220096
• 关键词: Adult; Age; Anxiety; Area; Atkins Diet; Basic Science; Behavior; Behavioral; Blood; Cells; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Data; Defect; Diet; Disease; Foundations; Genetic; Genetic Diseases; Handedness; Hippocampus (Brain); Histone Deacetylase; Histone Deacetylase Inhibitor; Impaired cognition; Impairment; Individual; Intellectual functioning disability; Kabuki Make-Up Syndrome; Ketones; Ketosis; Lead; Learning; Life; Link; Magnetic Resonance Imaging; Measures; Memory; Monitor; Mus; Mutation; Neurocognitive; Other Genetics; Outcome; Outcome Measure; Participant; Pathogenesis; Pathologic; Pathological anxiety; Patients; Performance; Phenotype; Pilot Projects; Population; Property; Prospective Studies; Protocols documentation; Proxy; Questionnaires; Radiology Specialty; Rare Diseases; Research; Techniques; Testing; Therapeutic; Translating; Urine; Variant; Visuospatial; Work; adult neurogenesis; behavioral outcome; brain volume; cognitive performance; cognitive testing; dentate gyrus; efficacy testing; granule cell; gray matter; improved; insight; ketogenic diet; loss of function; mouse model; neurobehavioral; neurobehavioral test; neurogenesis; neuroimaging; novel; postnatal; prospective; rare genetic disorder; recruit; sex; study population; treatment trial

Project Summary/Abstract Kabuki syndrome is a rare genetic disorder characterized by intellectual disability and a unique cognitive profile. Studies in a mouse model of Kabuki syndrome have demonstrated hippocampal memory defects and a disruption of adult neurogenesis in the the dentate gyrus. Interestingly, these deficits were normalized in postnatal life with agents that inhibit histone deacetylases, indicating that Kabuki syndrome may be a treatable cause of intellectual disability. Preliminary data shows that patients with Kabuki syndrome have deficits in visuospatial reasoning and memory and that these areas are significantly impaired when compared to IQ-matched controls. This proposal aims to build upon the basic science and clinical work to localize and characterize cognitive impairments in Kabuki syndrome and evaluate a potential treatment. If successful, these studies will yield insights into the pathogenesis of Kabuki syndrome and lead to the first therapeutic strategy. This work has the potential of establishing robust outcome measures and providing a novel treatment option to a clinical entity (intellectual disability) that has few therapeutic options. Specific Aim 1: Determine robust cognitive and behavioral outcome measures that are valid, reliable, and sensitive in a Kabuki syndrome population. This prospective study will investigate a Kabuki syndrome-specific cognitive assessment protocol linked to visuospatial functions and establish reliability and use established behavioral questionnaires to determine the neurobehavioral phenotype of Kabuki syndrome. Specific Aim 2: Characterize neuroanatomical features in patients with KMT2D mutations and provide further evidence of localization of specific impairments. This study done on a 3 Tesla MRI scanner will investigate whether patients with KMT2D mutations have smaller dentate gyri. Specific Aim 3: Test whether HDAC inhibition through modified Atkins diet modifies the neurocognitive or neurobehavioral phenotype in individuals with Kabuki syndrome. Previously, a ketogenic diet has been shown to ameliorate cognitive and neurohistological defects in a mouse model of Kabuki syndrome. This proposal aims to conduct a pilot study of 10 adult patients with Kabuki syndrome given 12 weeks of HDAC inhibition through diet and determine whether performance on the cognitive assessment protocol changes.

项目摘要/摘要 Kabuki综合征是一种罕见的遗传疾病，其特征是智力障碍和独特的遗传疾病 认知概况。在Kabuki综合征的小鼠模型中的研究已证明 海马记忆缺陷和齿状回中成年神经发生的破坏。 有趣的是，这些赤字在产后寿命中被标准化，抑制组蛋白的药物 脱乙酰基酶，表明Kabuki综合征可能是可治疗的智力原因 残疾。初步数据表明，Kabuki综合征的患者患有缺陷 视觉空间推理和记忆，当这些区域在 与IQ匹配的对照相比。该建议旨在以基础科学为基础 临床工作以本地化和表征卡布基综合征的认知障碍和 评估潜在的治疗方法。如果成功，这些研究将产生对 Kabuki综合征的发病机理，导致了第一种治疗策略。这项工作有 建立强大的结果度量并提供新颖的治疗选择的潜力 临床实体（智力残疾）几乎没有治疗选择。 特定目的1：确定强大的认知和行为结果指标 有效，可靠和敏感的Kabuki综合征人群。这项前瞻性研究将 研究与视觉空间有关的Kabuki综合征特异性认知评估协议 功能并建立可靠性并使用既定的行为问卷来确定 Kabuki综合征的神经行为表型。 特定目标2：表征KMT2D突变患者的神经解剖特征 并提供进一步的特定损害定位的证据。这项研究对 3特斯拉MRI扫描仪将研究KMT2D突变患者是否较小 齿回。 特定目的3：测试通过修改的Atkins饮食抑制HDAC是否会改变 Kabuki综合征个体中的神经认知或神经性表型。 以前，生酮饮食已被证明可以改善认知和神经组织学 在kabuki综合征的小鼠模型中的缺陷。该提案旨在进行10个试点研究 Kabuki综合征的成年患者通过饮食和 确定认知评估方案上的绩效是否改变。