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
基本信息
- 批准号:10661512
- 负责人:
- 金额:$ 16.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdultAgeAnxietyAreaAtkins DietBasic ScienceBehaviorBehavioralBloodCellsClinicalClinical ResearchClinical TrialsClinical Trials DesignCognitionCognitiveDataDefectDietDiseaseFoundationsGeneticGenetic DiseasesHandednessHippocampusHistone Deacetylase InhibitorImpaired cognitionImpairmentIndividualIntellectual functioning disabilityKabuki Make-Up SyndromeKetonesKetosesKetosisLearningLifeLinkMagnetic Resonance ImagingMeasuresMemoryMonitorMusMutationNeuroanatomyNeurocognitiveOther GeneticsOutcomeOutcome MeasureParticipantPathogenesisPathologicPathological anxietyPatientsPerformancePhenotypePilot ProjectsPopulationPropertyProspective StudiesProtocols documentationProxyQuestionnairesRadiology SpecialtyRare DiseasesResearchTechniquesTestingTherapeuticTranslatingUrineVariantVisuospatialWorkadult neurogenesisbehavioral outcomebrain volumecognitive performancecognitive testingdentate gyrusefficacy testinggranule cellgray matterimprovedinsightketogenic dietloss of functionmouse modelneurobehavioralneurobehavioral testneurogenesisneuroimagingnovelpostnatalprospectiverare genetic disorderrecruitsexstudy populationtreatment trial
项目摘要
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.
项目总结/摘要
歌舞伎综合征是一种罕见的遗传性疾病,其特征是智力残疾,
认知侧写对歌舞伎综合征小鼠模型的研究表明,
海马记忆缺陷和成年齿状回神经发生中断。
有趣的是,使用抑制组蛋白的药物后,这些缺陷在产后恢复正常
脱乙酰酶,这表明歌舞伎综合征可能是一个可治疗的原因,
残疾。初步数据显示,歌舞伎综合征患者在以下方面存在缺陷:
视觉空间推理和记忆,这些领域是显着受损时,
与智商匹配的对照组相比。这项建议旨在建立在基础科学和
临床工作定位和表征歌舞伎综合征的认知障碍,
评估潜在的治疗方法。如果成功的话,这些研究将深入了解
Kabuki综合征的发病机制,并导致第一个治疗策略。这项工作有
建立稳健的结局指标并为患者提供新的治疗选择的潜力
临床实体(智力残疾),几乎没有治疗选择。
具体目标1:确定稳健的认知和行为结果指标,
在歌舞伎综合征人群中有效、可靠和敏感。这项前瞻性研究将
探讨与视觉空间相关歌舞伎综合征特异性认知评估方案
功能和建立可靠性,并使用既定的行为问卷,以确定
歌舞伎综合征的神经行为表型
具体目标2:描述KMT 2D突变患者的神经解剖学特征
并进一步提供特定损伤定位的证据。这项研究是在一个
3特斯拉MRI扫描仪将调查KMT 2D突变患者是否具有较小的
齿状回
具体目标3:测试通过改良的阿特金斯饮食的HDAC抑制是否改变了HDAC。
在患有歌舞伎综合征的个体中的神经认知或神经行为表型。
以前,生酮饮食已被证明可以改善认知和神经组织学
Kabuki综合征小鼠模型的缺陷。该提案旨在对10个项目进行试点研究
通过饮食给予12周HDAC抑制的成年歌舞伎综合征患者,
确定认知评估方案的表现是否改变。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sleep disturbance is a common feature of Kabuki syndrome.
- DOI:10.1002/ajmg.a.62921
- 发表时间:2022-10
- 期刊:
- 影响因子:2
- 作者:Rapp, Tyler;Kalinousky, Allison J.;Johnson, Jennifer;Bjornsson, Hans;Harris, Jacqueline
- 通讯作者:Harris, Jacqueline
Genome-wide DNA methylation profiling confirms a case of low-level mosaic Kabuki syndrome 1.
- DOI:10.1002/ajmg.a.62754
- 发表时间:2022-07
- 期刊:
- 影响因子:2
- 作者:Montano, Carolina;Britton, Jacquelyn F.;Harris, Jacqueline R.;Kerkhof, Jennifer;Barnes, Benjamin T.;Lee, Jennifer A.;Sadikovic, Bekim;Sobreira, Nara;Fahrner, Jill A.
- 通讯作者:Fahrner, Jill A.
Neurobehavioral phenotype of Kabuki syndrome: Anxiety is a common feature.
- DOI:10.3389/fgene.2022.1007046
- 发表时间:2022
- 期刊:
- 影响因子:3.7
- 作者:
- 通讯作者:
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Jacqueline Harris其他文献
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{{ truncateString('Jacqueline Harris', 18)}}的其他基金
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 - 财政年份:2020
- 资助金额:
$ 16.84万 - 项目类别:
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:
10438767 - 财政年份:2020
- 资助金额:
$ 16.84万 - 项目类别:
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