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

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专注于从大脑中去除 β 淀粉样蛋白 (Aβ) 的治疗方法仍然难以捉摸。多态性与 AD/ADRD 之间建立了强关联的靶向基因，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。富含胆固醇的质膜结构变得稳定并扩大以容纳许多细胞的组装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，不破坏生理筏脂质在初步研究中，Apoa1bp-/- 小鼠与 TLR4 杂交。 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，AIBP- 大脑中的线粒体增加了。 APP/PS1 缺陷小鼠形态扭曲，具有特征性的超分枝和杯状形状，通常与腺相关病毒（AAV）介导的氧化应激相关。 Apoa1bp-/- APP/PS1 小鼠大脑中分泌的 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，以提供有效的治疗特别是在这个第一阶段 STTR 项目中，我们建议构建和优化 AD/ADRD 中的神经保护。 AAV-AIBP载体（RFT1041），将用于Aim 2的功效研究，预计进入IND- 我们将探索颅内和鞘内途径的开发。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、神经元此外，高级 EM 将用于评估细胞死亡、自噬、内质网应激和线粒体功能障碍。这些研究的结果将用于准备和进行线粒体形态和功能。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。