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Functional Validation of TDP-43 splicing repression for frontotemporal degeneration

TDP-43 剪接抑制对额颞叶变性的功能验证

基本信息

批准号：
9926573
负责人：
PHILIP C WONG
金额：
$ 146.28万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9926573
关键词：
Address Adult Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Attenuated Behavioral Binding Biological Models Cells Cognitive Cognitive deficits Complement Data Defect Dementia Disease Dose Elderly Etiology Excision Exhibits Exons Female Frontotemporal Dementia Gene Delivery Gene Expression Genes Human In Vitro Lewy Body Dementia Long-Term Effects Longevity Longitudinal Studies Mediating Modeling Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Pathogenesis Pathologic Pathology Patients Phase Phenotype Prosencephalon RNA Splicing Repression Role Small Interfering RNA Therapeutic Time Toxic effect Translating Translations Validation age related aged attenuation axon regeneration base frontotemporal degeneration gene product gene therapy human disease in vitro Model in vivo induced pluripotent stem cell insight male meetings mouse model neuron loss neuronal circuitry postnatal protein TDP-43 research clinical testing side effect therapeutic gene therapeutic target validation studies

项目摘要

Alzheimer's Disease-Related Dementias (ADRD) is a group of progressive neurodegenerative disorders with mid to late life onset such as FTLD-TDP or mixed etiology dementias (MED) including Alzheimer's disease (AD) with TDP-43 pathology. Human studies support the idea that loss of TDP-43 splicing repression underlies neuron loss in these disorders. We recently established that splicing repression is a major function of TDP-43 and validated TDP-43 repression as a promising therapeutic target for FTLD-TDP. By employing a comprehensive set of molecular, pathological, neuronal circuit and behavioral/cognitive approaches, we will functionally validate this type of AAV gene therapeutic strategy to complement TDP-43 repression using both in vivo mouse models and in vitro human iPSC derived neurons in the UG3 phase of the application. Upon meeting the Milestones for transition from UG3 to UH3 phase, we will determine: 1) the optimal dose of AAV gene expression the TDP-43 related repressor required to attenuate neuron loss while limiting any untoward side effects associated with long term exposure of this gene product; 2) the benefit of this AAV gene therapeutic strategy using our mouse model lacking TDP-43 in forebrain neurons in terms of attenuation of altered neuronal circuits, cognitive and behavioural deficits, and neurodegeneration; and 3) ability of AAV gene therapy to restore TDP-43 repression in cortical neurons derived from human iPSCs. Functional validation of TDP-43 repression will address a great unmet need for this type of ADRD.

阿尔茨海默病相关性痴呆（Alzheimer's Disease Related Dementias，ADRD）是一组进行性神经退行性疾病中晚期发病，如FTLD-TDP或混合病因痴呆（MED），包括阿尔茨海默病 (AD)TDP-43病理学人类研究支持TDP-43剪接抑制的缺失是神经元的丧失我们最近确定剪接抑制是TDP-43的主要功能并验证了TDP-43抑制作为FTLD-TDP的有希望的治疗靶点。通过采用一套全面的分子，病理，神经元电路和行为/认知方法，我们将功能上验证了这种类型的AAV基因治疗策略，以补充TDP-43抑制，体内小鼠模型和体外人iPSC衍生的神经元在UG 3阶段的应用。一见面 UG 3期向UH 3期转化的关键，我们将确定：1）AAV基因的最佳剂量表达TDP-43相关的阻遏物需要减弱神经元损失，同时限制任何不利的方面与该基因产物的长期暴露相关的作用; 2）该AAV基因治疗剂的益处使用我们的小鼠模型在前脑神经元中缺乏TDP-43的策略，回路、认知和行为缺陷以及神经变性;以及3）AAV基因治疗恢复神经元的能力，来源于人iPSC的皮质神经元中的TDP-43抑制。TDP-43抑制的功能验证将解决此类ADRD尚未满足的巨大需求。