Functional Validation of TDP-43 splicing repression for frontotemporal degeneration

阿尔茨海默病相关痴呆(ADRD)是一组进行性神经退行性疾病 中老年发病，如FTLD-TDP或混合病因痴呆(MED)，包括阿尔茨海默病 (AD)TDP-43病理切片。人体研究支持失去TDP-43剪接抑制的观点 这些疾病中的神经元丢失。我们最近发现，剪接抑制是TDP-43的一个主要功能 证实TDP-43抑制可作为FTLD-TDP的一个有前景的治疗靶点。通过雇用一名 一套全面的分子、病理、神经元回路和行为/认知方法，我们将 在功能上验证这种类型的AAV基因治疗策略以补充TDP-43抑制 体内小鼠模型和体外培养的人iPSC衍生神经元在UG3期的应用。一见钟情 从UG3向UH3过渡的里程碑，我们将确定：1)AAV基因的最佳剂量 表达TDP-43相关的抑制物，以减轻神经元的丢失，同时限制任何不良反应 与长期接触该基因产物有关的影响；2)这种AAV基因治疗的益处 利用我们的小鼠前脑神经元缺失TDP-43模型对改变的神经元进行衰减的策略 回路、认知和行为缺陷以及神经变性；以及3)AAV基因治疗恢复的能力 人IPSCs来源的皮质神经元中TDP-43的抑制。TDP-43抑制基因的功能验证 将解决这种类型的ADRD尚未得到满足的巨大需求。

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.