Defining the Potential of Gene Therapy to Correct Motor Disabilities of CTNNB1 Syndrome Using in Vivo Mouse and in Vitro Human Cell Models
利用体内小鼠和体外人类细胞模型确定基因疗法纠正 CTNNB1 综合征运动障碍的潜力
基本信息
- 批准号:10809254
- 负责人:
- 金额:$ 45.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-25 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Adverse effectsBehaviorBindingBiological AssayCTNNB1 geneCancer EtiologyCapsidCell modelChildChildhoodChronicClinical TrialsCognitiveDataDevelopmental Delay DisordersDiseaseDistalDoseDuchenne muscular dystrophyEnzyme InhibitionExhibitsFamilyFelis catusGene MutationGenerationsGenesGlycogen Synthase KinasesGoalsHalf-LifeHand StrengthHeterozygoteHumanImpaired cognitionIn VitroIntellectual functioning disabilityK ATPaseLanguageLearningLegLifeLiverMeasuresMedicalMessenger RNAModelingMolecularMonitorMotorMotor NeuronsMusMuscleMuscle CellsMuscle FibersMuscle HypertoniaMuscle hypotoniaMyopathyNational Institute of Neurological Disorders and StrokeNeuronsNonprofit OrganizationsOutcomePF4 GeneParentsPathogenicityPatientsPerformancePharmacotherapyPhenotypePitt-Hopkins syndromePre-Clinical ModelPresynaptic TerminalsProteinsQuality of lifeRelaxationReportingResearch PersonnelRisk ReductionSafetySignal TransductionSignaling MoleculeSkeletal MuscleSpastic GaitSyndromeTestingTherapeuticToxic effectVariantViralViral GenesWalkingWestern BlottingWheelchairsbehavior testcancer riskcell typecognitive disabilitydesigndevelopmental diseasedisabilitygene therapyhuman modelimprovedin vivoinduced pluripotent stem cellinhibitorinsightloss of functionmotor impairmentmotor learningmouse modelmuscle strengthneuromuscularnext generationnonhuman primatereduced muscle strengthresponsesmall moleculesmall molecule inhibitorspasticitytherapeutic evaluationtherapeutically effectivetherapy outcometranscription factortransduction efficiencytransgene expressionyoung adult
项目摘要
CTNNB1 syndrome is an incapacitating developmental disorder characterized by intellectual disabilities, global
developmental delays (motor, language) and motor disabilities (truncal muscle hypotonia, distal muscle
hypertonia, spasticity, reduced muscle strength). The children have spastic gait or inability to walk, severely
impacting their quality of life. Their parents prioritize their being able to walk. No treatments are currently
available. The syndrome is caused by CTNNB1 (-catenin) haploinsufficiency due to de novo pathogenic
variants causing partial or complete deletions. Because it is a monogenetic disorder, we propose the first tests,
as proof-of-concept, that gene therapy can provide effective and safe therapeutic outcomes. We propose that
gene therapy will improve the reduced -catenin levels and significantly remedy the phenotypes. We will test our
hypothesis using two preclinical models of CTNNB1 heterozygosity, our in vivo mouse line and human iPSC
derived myotubes, a human cell type relevant to the motor disabilities of this syndrome. We will use newly
developed, next-generation muscle tropic AAVs to express CTNNB1/-catenin in the heterozygote models. New
studies report that one treatment with these AAVs provides safe, effective and long-lasting transgene expression
in mouse and non-human primate skeletal muscles in vivo and human myotubes in vitro, and significantly
remedies the phenotypes of two different neuromuscular myopathies in mice. Our CTNNB1 global heterozygote
mouse exhibits motor and cognitive impairments that resemble key features of CTNNB1 syndrome in children.
The motor impairments include reduced motor learning, coordination, and grip strength, relative to wildtype
littermates. We also find molecular changes in the het muscle consisting of altered levels of proteins that regulate
contractility, relaxation, and force in working muscle. Further, we find reduced levels of a muscle-derived
retrograde signaling factor required for normal motor neuron presynaptic terminal maturation. Our Aim 1 studies
will test whether direct transgene expression of CTNNB1 will improve -catenin levels in the CTNNB1 het mouse
skeletal muscle in vivo and human myotubes. Our dose-response tests will identify the lowest viral doses that
increase the reduced -catenin levels in the het models, test duration of the improved levels after the single
treatment, and absence of adverse effects. Our goal is to increase -cat levels in the mouse and human het
muscle cells, to resemble the normal baseline ranges of wildtype littermates and isogenic revertant control
myotubes, respectively. Aim 2 will test for statistically significant improvements in motor capabilities in vivo and in
molecular changes in the gene therapy treated mouse and human het models. We will use quantitative behavior
assays, immunoblotting and RT-qPCR. Our studies will provide the first insights into the efficacy and safety of
gene therapy for remedying pathophysiological changes caused by CTNNB1 haploinsufficiency. These critical
proof-of-concept studies in two preclinical models will inform the design of therapeutic strategies to provide life
altering benefits to children with CTNNB1 syndrome.
CTNNB 1综合征是一种以智力残疾为特征的失能性发育障碍,全球
发育迟缓(运动、语言)和运动残疾(躯干肌张力减退、远端肌张力减退)
张力亢进、痉挛状态、肌力降低)。孩子们有痉挛性步态或无法行走,严重的
影响他们的生活质量。他们的父母优先考虑他们能够走路。目前没有治疗方法
available.该综合征是由CTNNB 1(β-连环蛋白)单倍不足引起的,
导致部分或完全缺失的变体。因为这是一种单基因遗传疾病,我们提出了第一个测试,
作为概念验证,基因治疗可以提供有效和安全的治疗结果。我们建议
基因治疗将改善降低的β-连环蛋白水平并显著纠正表型。我们将测试我们的
使用CTNNB 1杂合性的两种临床前模型,我们的体内小鼠系和人iPSC
衍生的肌管,一种与该综合征的运动障碍相关的人类细胞类型。我们将使用新的
开发了下一代肌肉嗜性AAV以在杂合子模型中表达CTNNB 1/β-连环蛋白。新
研究报道,用这些AAV的一种治疗提供安全、有效和持久的转基因表达,
在小鼠和非人灵长类动物体内骨骼肌和体外人肌管中,
治疗小鼠中两种不同神经肌肉肌病的表型。我们的CTNNB 1全杂合子
小鼠表现出类似于儿童CTNNB 1综合征的关键特征的运动和认知障碍。
相对于野生型,运动障碍包括运动学习、协调和握力降低
同窝出生的我们还发现het肌肉中的分子变化包括调节蛋白质水平的改变,
收缩性、松弛性和工作肌肉的力量。此外,我们发现肌肉来源的
正常运动神经元突触前终末成熟所需的逆行信号因子。我们的Aim 1研究
将测试CTNNB 1的直接转基因表达是否会提高CTNNB 1 het小鼠中β-连环蛋白水平
体内骨骼肌和人肌管。我们的剂量反应测试将确定最低的病毒剂量,
增加het模型中降低的β-连环蛋白水平,单次给药后改善水平的测试持续时间
治疗,无不良反应。我们的目标是增加小鼠和人类het中的het-cat水平,
肌细胞,以类似于野生型同窝仔和同基因回复突变体对照的正常基线范围
肌管。目标2将测试体内和体内运动能力的统计学显著改善。
基因治疗处理的小鼠和人HET模型中的分子变化。我们将使用定量行为
测定、免疫印迹和RT-qPCR。我们的研究将首次深入了解
基因治疗用于治疗由CTNNB 1单倍不足引起的病理生理变化。这些关键
在两个临床前模型中进行的概念验证研究将为治疗策略的设计提供信息,
改变CTNNB 1综合征患儿的获益。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michele H. Jacob其他文献
Use of polyadenosine tail mimetics to enhance mRNA expression from genes associated with haploinsufficiency disorders
使用多聚腺苷酸尾巴模拟物来增强与单倍体不足症相关基因的 mRNA 表达
- DOI:
10.1016/j.omtn.2025.102453 - 发表时间:
2025-03-11 - 期刊:
- 影响因子:6.100
- 作者:
Bahareh Torkzaban;Yining Zhu;Christian Lopez;Jonathan M. Alexander;Jingyao Ma;Yongzhi Sun;Katharine R. Maschhoff;Wenqian Hu;Michele H. Jacob;Dingchang Lin;Hai-Quan Mao;Sophie Martin;Jeff Coller - 通讯作者:
Jeff Coller
Michele H. Jacob的其他文献
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{{ truncateString('Michele H. Jacob', 18)}}的其他基金
Investigating molecular mechanisms and treatments for CTNNB1 Syndrome using mouse and human models
使用小鼠和人类模型研究 CTNNB1 综合征的分子机制和治疗方法
- 批准号:
10307411 - 财政年份:2021
- 资助金额:
$ 45.38万 - 项目类别:
Molecular causes of cognitive and autistic disabilities
认知障碍和自闭症障碍的分子原因
- 批准号:
9026843 - 财政年份:2016
- 资助金额:
$ 45.38万 - 项目类别:
Molecular causes of cognitive and autistic disabilities
认知障碍和自闭症障碍的分子原因
- 批准号:
9917856 - 财政年份:2016
- 资助金额:
$ 45.38万 - 项目类别:
Molecular causes of cognitive and autistic disabilities
认知障碍和自闭症障碍的分子原因
- 批准号:
9326368 - 财政年份:2016
- 资助金额:
$ 45.38万 - 项目类别:
Molecular mechanisms of auditory nAChR synapse assembly
听觉 nAChR 突触组装的分子机制
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- 资助金额:
$ 45.38万 - 项目类别:
Molecular mechanisms of auditory nAChR synapse assembly
听觉 nAChR 突触组装的分子机制
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8317687 - 财政年份:2009
- 资助金额:
$ 45.38万 - 项目类别:
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