Somatostatin (SST)-GABAergic Interneuron Therapy for Alzheimer's Disease with ApoE4

生长抑素 (SST)-GABA 能中间神经元治疗 ApoE4 治疗阿尔茨海默病

• 批准号: 10011752
• 负责人: ROBERT W. MAHLEY
• 金额: $ 94.86万
• 依托单位: GABAERON, INC.
• 依托单位国家: 美国
• 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/10011752
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Animal Model; Apolipoprotein E; Brain; Brain region; Cells; Cessation of life; Clinical; Cognition; Complex; Consensus; Derivation procedure; Development; Disease; Dose; Event; Failure; Genotype; Goals; Heterogeneity; Hippocampus (Brain); Human; Human Amyloid Precursor Protein; Impairment; Individual; Interneurons; Knock-in; Knock-in Mouse; Lead; Learning; Memory; Memory impairment; Mus; Mutation; Neurodegenerative Disorders; Neurons; Pathway interactions; Patients; Pharmaceutical Preparations; Protein Isoforms; Protocols documentation; Replacement Therapy; Somatostatin; Testing; Therapeutic; Transplantation; United States; abeta accumulation; aged; apolipoprotein E-3; apolipoprotein E-4; base; disease-causing mutation; familial Alzheimer disease; genetic risk factor; induced pluripotent stem cell; memory process; neuron loss; novel; patient population; patient stratification; progenitor; safety testing; stem cells; targeted treatment; therapeutic candidate; therapy development; traditional therapy

PROJECT SUMMARY (FAST-TRACK APPLICATION) Alzheimer’s disease (AD) is a neurodegenerative disorder affecting over 5.4 million individuals in the United States alone. Carriers of apolipoprotein (apo) E4, one of the three apoE isoforms (apoE2, apoE3, apoE4), are associated with 60–80% of all AD cases, making apoE4 the major genetic risk factor for AD. As a complex disease that causes early damage to the hippocampus, a brain region essential for cognition, AD presents unique challenges for developing traditional therapies. To date, all efforts to develop therapies that target specific AD-related pathways have failed in human trials of late-stage AD. As a result, an emerging consensus in the field is that treatment of patients with mild or moderate AD with current drugs comes too late, likely due to significant neuronal loss in the brain, especially in the hippocampus. In this regard, induced pluripotent stem cells (iPSCs) provide a way to generate human neurons or their progenitors for cell-replacement therapy. However, currently limited iPSC-based therapeutic approaches under development for potential AD treatment do not consider apoE4’s impact, which could lead to clinical failure due to patient heterogeneity and/or apoE4’s detrimental effects. By using apoE4 allelic expression to stratify patients, we will be able to create a defined patient population (apoE4-positive AD patients) for testing a matched disease-modifying treatment [human iPSC-derived somatostatin (SST)-positive GABAergic interneurons with an apoE3/3 genotype]. This proposal builds on five novel findings from our recent studies in animal models of AD and in human iPSC-derived neurons. First, apoE4 causes SST-GABAergic interneuron loss in the hippocampal hilus, which correlates with the impairment of hippocampal network activity and the extent of learning and memory deficits. Second, apoE4 causes the selective death of human iPSC–derived SST-GABAergic interneurons in culture. Third, the detrimental effect of apoE4 on SST-GABAergic interneurons is cell autonomous. Fourth, transplantation of mouse GABAergic interneuron progenitors into the hippocampal hilus restores normal learning and memory in aged apoE4 knock-in (apoE4-KI) mice without or with Aβ accumulation. Fifth, transplantation of human iPSC- derived GABAergic interneuron progenitors into the hippocampal hilus restores normal learning and memory in aged apoE4-KI mice. The goals of this proposal are 1) to develop and optimize a protocol for the robust derivation of SST-GABAergic interneurons from human iPSCs with an apoE3/3 genotype, 2) to determine the desired dose and test the safety and efficacy of transplanting human iPSC-derived SST-GABAergic interneurons into the hippocampal hilus to restore normal learning and memory in aged apoE4-KI mice, and 3) to test the safety and efficacy of transplanting human iPSC-derived SST-GABAergic interneurons into the hippocampal hilus to restore normal learning and memory in apoE4-KI mice expressing human amyloid precursor protein (APP) with mutations that cause familial AD (FAD) (hAPPFAD).

项目概要（快速通道申请） 阿尔茨海默病（AD）是一种神经退行性疾病，在美国影响超过540万人。 只有国家。载脂蛋白（apo）E4是三种apoE亚型（apoE 2，apoE 3，apoE 4）之一， 与60-80%的AD病例相关，使apoE 4成为AD的主要遗传风险因素。作为一个复杂 AD是一种导致海马体早期损伤的疾病，海马体是认知所必需的大脑区域，AD表现为 发展传统疗法的独特挑战。迄今为止，所有开发靶向治疗的努力， 特定的AD相关途径在晚期AD的人体试验中失败了。因此，一个正在形成的共识是， 目前的药物治疗轻度或中度AD患者为时已晚，可能是由于 大脑中的神经元严重缺失，尤其是海马体。在这方面，诱导多能干细胞 多能干细胞（iPSC）提供了一种产生人类神经元或其祖细胞用于细胞替代疗法的方法。 然而，目前有限的基于iPSC的治疗方法正在开发中，用于潜在的AD治疗。 不考虑apoE 4的影响，由于患者异质性和/或apoE 4的 有害影响。通过使用apoE 4等位基因表达对患者进行分层，我们将能够创建一个定义的 用于测试匹配的疾病改善治疗的患者群体（apoE 4阳性AD患者）[人 具有apoE 3/3基因型的iPSC衍生的生长抑素（SST）阳性GABA能中间神经元]。这项建议 基于我们最近在AD动物模型和人类iPSC衍生的研究中的五项新发现， 神经元首先，apoE 4导致海马门区SST-GABA能中间神经元丢失，这与 海马网络活动受损和学习记忆障碍的程度。第二，apoE 4 导致培养物中人iPSC衍生的SST-GABA能中间神经元的选择性死亡。三是 apoE 4对SST-γ-氨基丁酸能中间神经元有害作用是细胞自主的。第四，移植 小鼠GABA能中间神经元祖细胞进入海马门恢复正常的学习和记忆， 无或有Aβ蓄积的apoE 4-KI老年小鼠。第五，人类iPSC的移植- GABA能中间神经元前体细胞进入海马门后恢复正常的学习和记忆。 老年apoE 4-KI小鼠。该提案的目标是：1）开发和优化一种用于鲁棒的 从具有apoE 3/3基因型的人iPSC衍生SST-GABA能中间神经元，2）以确定 并测试移植人iPSC衍生的SST-GABA能的安全性和功效 3）在老年apoE 4-KI小鼠中，将中间神经元引入海马门以恢复正常的学习和记忆，以及 为了测试将人iPSC衍生的SST-GABA能中间神经元移植到人骨髓中的安全性和有效性， 海马门对表达人淀粉样蛋白的apoE 4-KI小鼠恢复正常学习和记忆的作用 前体蛋白（APP）突变导致家族性AD（FAD）（hAPPFAD）。