AAV-AIBP Therapy for Alzheimer's Disease

AAV-AIBP 治疗阿尔茨海默病

• 批准号: 10604136
• 负责人: WONKYU JU
• 金额: $ 24.71万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604136
• 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; Dependovirus; Development; Dose; Elements; Ensure; Evaluation Research; Excision; Feedback; Fibronectins; Genes; Genetic Polymorphism; Goals; Human; In Situ Nick-End Labeling; Inflammation; Inflammatory; Inflammatory Response; Injections; Learning; 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; Proteins; Radial; 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; arm; base; behavior test; brain tissue; clinical application; clinical development; effective therapy; efficacy study; efficacy testing; endoplasmic reticulum stress; gene therapy; 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.

项目总结 阿尔茨海默病和相关痴呆的治疗(AD/ADRD)，进展缓慢的神经退行性变 疾病，仍然难以捉摸。专注于从大脑或其他部位移除β淀粉样蛋白(Aβ)的治疗方法 靶向基因的多态与AD/ADRD有很强的关联，有 他的成功记录好坏参半。我们提出了一种新的策略来逆转AD/ADRD相关性神经炎 通过靶向炎症细胞和活化细胞中的病理性脂筏而导致线粒体功能障碍。这些 富含胆固醇的质膜结构变得稳定和扩大，以容纳许多 炎性受体和其他分子参与导致神经细胞死亡的病理过程 和神经退化。我们已经确定apoA-I结合蛋白(AIBP，由Apoa1BP基因编码)是关键 细胞胆固醇代谢调节剂，可通过结合到病理性脂筏而选择性地靶向 TLR4，不破坏生理脂筏。在初步研究中，Apoa1BP-/-小鼠与 APP/PS1转基因小鼠出现更多的Aβ斑块，一种加重的功能障碍的小胶质细胞表型和 与APP/PS1小鼠相比，神经细胞死亡增加。此外，AIBP-脑中的线粒体- APP/PS1缺陷小鼠形态扭曲，呈典型的超枝状和杯状， 通常与氧化应激有关。腺相关病毒(AAV)介导的A基因过表达 Apoa1BP-/-APP/PS1小鼠脑内分泌形式的AIBP恢复了小胶质细胞的动态平衡表型。 RAFT制药公司建议开发一种基于AAV-AIBP的疗法，以提供有效的 AD/ADRD的神经保护。具体地说，在这个第一阶段的STTR项目中，我们建议构建和优化 AAV-AIBP载体(RFT1041)，该载体将用于AIM 2的疗效研究，并有望进入IND-2。 使人类临床应用的开发成为可能。我们将探索颅内和鞘内途径 给药并测试单次注射AAV-AIBP是否在大脑中实现持续的AIBP表达。的功效。 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、变化 在记忆和学习中，Aβ斑块和tau缠结的范围，小胶质细胞的激活，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，还将使用高级EM来评估 线粒体的形态和功能。这些研究的结果将被用来准备和进行 与FDA进行互动会议，以获得FDA对拟议开发计划的初步反馈 并协助最大限度地减少产品开发所花费的时间，缩短产品上市时间。