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

基本信息

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
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/10011752
关键词：
Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos 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

项目摘要

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).

项目摘要（快速申请）阿尔茨海默病 (AD) 是一种神经退行性疾病，影响着美国超过 540 万人载脂蛋白 (apo) E4（三种 apoE 亚型（apoE2、apoE3、apoE4）之一）的单独状态。与 60-80% 的 AD 病例相关，这使得 apoE4 成为 AD 的主要遗传风险因素。 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迄今为止，开发传统疗法的独特挑战。特定的 AD 相关途径在晚期 AD 的人体试验中失败了，因此，正在形成共识。该领域的一个问题是，用现有药物治疗轻度或中度 AD 患者来得太晚，可能是由于导致大脑中，特别是海马中的显着神经元损失，在这方面，诱导多能干。细胞（iPSC）提供了一种产生人类神经元或其祖细胞以用于细胞替代疗法的方法。然而，目前正在开发的基于 iPSC 的潜在 AD 治疗方法有限不考虑 apoE4 的影响，这可能会因患者异质性和/或 apoE4 的影响而导致临床失败通过使用 apoE4 等位基因表达对患者进行分层，我们将能够创建一个明确的影响。患者群体（apoE4 阳性 AD 患者），用于测试匹配的疾病缓解治疗 [人类 iPSC 衍生的生长抑素 (SST) 阳性 GABA 能中间神经元，具有 apoE3/3 基因型]。基于我们最近对 AD 动物模型和人类 iPSC 衍生的研究的五项新发现首先，apoE4 导致海马门中 SST-GABA 能中间神经元丢失，这与相关。海马网络活动受损以及学习和记忆缺陷的程度第二，apoE4。导致培养物中人类 iPSC 衍生的 SST-GABA 能中间神经元的选择性死亡。 apoE4 对 SST-GABA 能中间神经元的应激作用是细胞自主的。小鼠 GABA 能中间神经元祖细胞进入海马门可恢复正常学习和记忆没有或有Aβ积累的老年apoE4敲入（apoE4-KI）小鼠第五，移植人iPSC-。衍生的 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该提案的目标是 1) 开发和优化稳健的实验方案。从具有 apoE3/3 基因型的人 iPSC 中衍生出 SST-GABA 能中间神经元，2) 以确定所需剂量并测试移植人类 iPSC 衍生的 SST-GABAergic 的安全性和有效性将中间神经元插入海马门以恢复老年 apoE4-KI 小鼠的正常学习和记忆，以及 3) 测试将人 iPSC 衍生的 SST-GABA 能中间神经元移植到海马门恢复表达人类淀粉样蛋白的 apoE4-KI 小鼠的正常学习和记忆具有导致家族性 AD (FAD) (hAPPFAD) 突变的前体蛋白 (APP)。