AAV-AIBP Therapy for Alzheimer's Disease

AAV-AIBP 治疗阿尔茨海默病

• 批准号: 10708176
• 负责人: WONKYU JU
• 金额: $ 25.29万
• 依托单位: RAFT PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708176
• 关键词: 3xTg-AD mouse; APP-PS1; ATF6 gene; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Model; Apolipoprotein A-I; Autophagocytosis; Behavioral; Bilateral; Binding; Binding Proteins; Biological Products; Brain; Brain Pathology; Cell membrane; Cells; Characteristics; Cholesterol; Cholesterol Homeostasis; DLG4 gene; Dependovirus; Development; Dose; EIF-2alpha; Elements; Ensure; Evaluation; Excision; Feedback; Fibronectins; Genes; Genetic Polymorphism; Goals; Human; In Situ Nick-End Labeling; Inflammation; Inflammatory; Inflammatory Response; Injections; Learning; Marketing; Mediating; Membrane; Membrane Microdomains; Memory; Methods; Microglia; Mitochondria; Morphology; Mus; Neonatal; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; OPA1 gene; Oxidative Stress; Pathologic; Pathologic Processes; Patients; Pattern; Peptide Signal Sequences; Pharmacologic Substance; Phase; Phenotype; Physiological; Play; Program Development; Protein Deficiency; Proteins; Radial; Research; Role; Route; Senile Plaques; Shapes; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Survival Rate; Synaptophysin; TLR4 gene; Testing; Therapeutic; Time; Transgenic Mice; Virus; Western Blotting; arm; behavior test; brain tissue; clinical application; clinical development; effective therapy; efficacy study; efficacy testing; endoplasmic reticulum stress; gene therapy; improved; meetings; mitochondrial dysfunction; mouse model; neuroinflammation; neuron loss; neuroprotection; novel; novel strategies; novel therapeutic intervention; overexpression; product development; protein distribution; protein expression; receptor; recruit; scaffold; success; tau Proteins; vector; water maze

PROJECT SUMMARY Therapy for Alzheimer’s disease and related dementias (AD/ADRD), slow-progressing neurodegenerative diseases, remains elusive. Therapeutic approaches focusing on beta amyloid (Aβ) removal from the brain or on targeting genes for which strong associations between their polymorphism and AD/ADRD are established, have had a mixed record of success. We propose a novel strategy to reverse AD/ADRD associated neuroinflammation and mitochondrial dysfunction via targeting pathological lipid rafts in inflammatory and activated cells. These cholesterol-rich plasma membrane structures become stable and enlarged to host the assembly of many inflammatory receptors and other molecules involved in pathological processes leading to neuronal cell death and neurodegeneration. We have identified apoA-I binding protein (AIBP, encoded by Apoa1bp gene) as a key regulator of cellular cholesterol metabolism, which can selectively target pathological lipid rafts via its binding to TLR4, without damaging physiological lipid rafts. In preliminary studies, the Apoa1bp-/- mice crossed with APP/PS1 transgenic mice presented more Aβ plaques, an exacerbated dysfunctional microglia phenotype and increased neuronal cell death when compared to APP/PS1 mice. In addition, mitochondria in the brain of AIBP- deficient APP/PS1 mice were morphologically distorted, with a characteristic hyper-branched and cupped shape, typically associated with oxidative stress. The adeno-associated virus (AAV)-mediated overexpression of a secreted form of AIBP in the brain of Apoa1bp-/- APP/PS1 mice restored the microglial homeostatic phenotype. RAFT Pharmaceuticals proposes the development of an AAV-AIBP based therapy to provide effective neuroprotection in AD/ADRD. Specifically in this Phase 1 STTR project, we propose to construct and optimize an AAV-AIBP vector (RFT1041), which will be used in efficacy studies of Aim 2 and is expected to enter IND- enabling development for human clinical applications. We will explore intracranial and intrathecal routes of delivery and test if a single AAV-AIBP injection achieves sustained AIBP expression in the brain. The efficacy of RFT1041 (3 different doses) will be tested in APP/PS1 and 3xTg mouse models to evaluate survival, changes in memory and learning, the extent of Aβ plaques and tau tangles, microglia activation, synaptotoxicity, neuronal cell death, autophagy, ER stress, and mitochondrial dysfunction. In addition, advanced EM will be used to assess mitochondrial morphology and function. Results of these studies will be used to prepare for and conduct an INTERACT meeting with the FDA to receive preliminary FDA feedback on the proposed development program and assists in minimizing the time spent in product development and reduce time to market.

项目概要 治疗阿尔茨海默病和相关痴呆症 (AD/ADRD)、缓慢进展的神经退行性疾病 疾病，仍然难以捉摸。治疗方法侧重于从大脑中去除 β 淀粉样蛋白 (Aβ) 或 多态性与 AD/ADRD 之间建立了强关联的靶向基因， 成功的记录有好有坏。我们提出了一种逆转 AD/ADRD 相关神经炎症的新策略 通过靶向炎症细胞和活化细胞中的病理性脂筏来治疗线粒体功能障碍。这些 富含胆固醇的质膜结构变得稳定并扩大以容纳许多 炎症受体和其他参与导致神经细胞死亡的病理过程的分子 和神经退行性变。我们已经确定apoA-I结合蛋白（AIBP，由Apoa1bp基因编码）作为关键 细胞胆固醇代谢的调节剂，可以通过结合选择性地靶向病理性脂筏 TLR4，不破坏生理脂筏。在初步研究中，Apoa1bp-/- 小鼠与 APP/PS1 转基因小鼠呈现出更多的 Aβ 斑块、加剧的功能失调的小胶质细胞表型和 与 APP/PS1 小鼠相比，神经元细胞死亡增加。此外，AIBP 大脑中的线粒体 APP/PS1 缺陷小鼠形态扭曲，具有特征性的超分枝和杯状形状， 通常与氧化应激有关。腺相关病毒（AAV）介导的过表达 Apoa1bp-/- APP/PS1 小鼠大脑中分泌形式的 AIBP 恢复了小胶质细胞稳态表型。 RAFT Pharmaceuticals 提议开发基于 AAV-AIBP 的疗法，以提供有效的治疗 AD/ADRD 中的神经保护。具体来说，在 STTR 第一阶段项目中，我们建议构建和优化 AAV-AIBP载体（RFT1041），将用于Aim 2的功效研究，预计进入IND- 促进人类临床应用的开发。我们将探索颅内和鞘内途径 递送并测试单次 AAV-AIBP 注射是否能在大脑中实现持续的 AIBP 表达。功效 RFT1041（3种不同剂量）将在APP/PS1和3xTg小鼠模型中进行测试，以评估存活率、变化 在记忆和学习方面，Aβ 斑块和 tau 蛋白缠结的程度、小胶质细胞激活、突触毒性、神经元 细胞死亡、自噬、内质网应激和线粒体功能障碍。此外，先进的 EM 将用于评估 线粒体的形态和功能。这些研究的结果将用于准备和进行 与 FDA 举行 INTERACT 会议，以获得 FDA 对拟议开发计划的初步反馈 并有助于最大限度地减少产品开发时间并缩短上市时间。