AAV-AIBP Therapy for Alzheimer's Disease

AAV-AIBP 治疗阿尔茨海默病

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos 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

3xTg-AD mouse APP-PS1 ATF6 gene Age Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos 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

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项目摘要

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.

项目摘要阿尔茨海默氏病和相关痴呆症（AD/ADRD）的治疗，较慢的神经退行性疗法疾病，仍然难以捉摸。从大脑或上取出β淀粉样β淀粉样蛋白（Aβ）的治疗方法建立了其多态性与AD/ADRD之间强烈关联的靶向基因，已有成功的记录不同。我们提出了一种逆转AD/ADRD相关神经炎症的新型策略和线粒体功能障碍通过靶向炎症和活化细胞中的病理脂质筏。这些富含胆固醇的质膜结构变得稳定并扩大，以容纳许多导致神经元细胞死亡的病理过程涉及的炎症受体和其他分子和神经变性。我们已经将apoA-i结合蛋白（AIBP，由apoa1bp基因编码）确定为键细胞胆固醇代谢的调节剂，可以通过其结合选择性地靶向病理脂质筏 TLR4，没有损坏物理脂质筏。在初步研究中，apoA1bp - / - 小鼠与 APP/PS1转基因小鼠提出了更多的Aβ斑块，一种恶化的功能障碍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-大脑中的线粒体缺陷的APP/PS1小鼠在形态上扭曲，具有特征性的超支和杯形的形状，通常与氧化应激有关。与腺相关病毒（AAV）介导的A的过表达 APOA1BP - / - APP/PS1小鼠大脑中AIBP的分泌形式恢复了小胶质体稳态表型。 RAFT Pharmaceuticals建议开发基于AAV-AIBP的疗法，以提供有效 AD/ADRD中的神经保护作用。特别是在此阶段1 STTR项目中，我们建议构建和优化 AAV-AIBP矢量（RFT1041）将用于AIM 2的效率研究，并有望进入为人类临床应用提供发展。我们将探索颅内和鞘内途径输送和测试是否单个AAV-AIBP注射能够实现大脑中的AIBP表达。效率 RFT1041（3种不同剂量）将在APP/PS1和3XTG鼠标模型中进行测试，以评估生存，变化在记忆和学习中，Aβ斑块和tau缠结，小胶质细胞激活，突触毒素，神经元的程度细胞死亡，自噬，ER应力和线粒体功能障碍。此外，高级EM将用于评估 mitochondrial morphology and function.这些研究的结果将用于准备和进行与FDA的互动会议，以接收有关拟议开发计划的初步FDA反馈并有助于最大程度地减少产品开发中所花费的时间并减少上市时间。