Functional Validation of TDP-43 splicing repression for frontotemporal degeneration

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UG3阶段的应用。一见面 UG3期向UH3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 将解决这类ADRD的巨大未满足需求。

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.