Development of AAV-AIBP for neuroprotection in glaucoma

用于青光眼神经保护的 AAV-AIBP 的开发

基本信息

批准号：
10680277
负责人：
WONKYU JU
金额：
$ 77.68万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680277
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Apolipoprotein A-I Automobile Driving Axon Binding Proteins Biological Blindness California Cell Death Cell Survival Cell model Cells Cholesterol Cholesterol Homeostasis Clinical Cyclic GMP Dependovirus Development Disease Disease Progression Dose Elements Ensure Eye Fibronectins Genes Genetic Polymorphism Glaucoma Human Hydrostatic Pressure Individual Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Intervention Link Membrane Microdomains Microglia Microspheres Mitochondria Modeling Muller&apos s cell Mus NOEL Nerve Crush Nerve Degeneration Neuroglia No-Observed-Adverse-Effect Level Ocular Hypertension Optic Nerve Organ Pathogenesis Pathogenicity Pathology Patients Pattern Peptide Signal Sequences Pharmacologic Substance Phase Physiologic Intraocular Pressure Primary Open Angle Glaucoma Process Protein Secretion Proteins Rattus Recombinants Research Retina Retinal Ganglion Cells Risk Risk Factors Safety TLR4 gene Testing Time Toxic effect Toxicology United States National Institutes of Health University resources Vision Visual Acuity cholesterol transporters clinical application clinical development dimer first-in-human gene therapy glial activation immunogenicity improved in vivo inflammatory marker manufacture mitochondrial dysfunction mouse model neuroinflammation neuroprotection novel pre-Investigational New Drug meeting preservation primary outcome protein distribution protein expression receptor response restoration standard of care targeted treatment vector visual dysfunction

项目摘要

Glaucoma is a leading cause of blindness worldwide. Emerging evidence suggests that glia-neuroinflammation is a critical element driving retinal ganglion cell (RGC) death and optic nerve degeneration in the pathogenesis of glaucoma. Gene polymorphisms in toll-like receptor-4 (TLR4, inflammatory receptor) and ATP-binding cassette transporter A1 (ABCA1, cellular cholesterol transporter) are linked to the risk of primary open-angle glaucoma. Our studies demonstrated increased TLR4 and reduced ABCA1 expression in RGCs and glia in human glaucomatous retina. We identified the secreted apoA-I binding protein (AIBP; gene APOA1BP) as a key regulator of cellular cholesterol metabolism, which controls TLR4 activation via ABCA1-dependent cholesterol depletion from TLR4 occupied lipid rafts in inflammatory and activated cells. Similar to ABCA1, AIBP expression was reduced, while cholesterol levels and inflammatory markers increased in human and mouse glaucomatous retinas. Apoa1bp-/- mice had compromised visual acuity and compared to wild type, had increased retinal TLR4 and IL-1β expression, augmented microglial activation, and increased RGC death in response to elevated intraocular pressure (IOP). These findings support the rationale for restoration of AIBP expression in the retina to provide sustained neuroprotection in patients with glaucoma. In preliminary studies, adeno-associated virus (AAV)-AIBP protected RGCs and ameliorated visual dysfunction in experimental mouse models of glaucoma. In addition, recombinant AIBP protein promoted mitochondrial function as well as inhibited inflammatory responses in cultured Müller glia and microglia in response to elevated hydrostatic pressure. Based on our previous and these findings, we propose development of AAV2-hAIBP based therapy to reduce retinal neuroinflammation and provide effective neuroprotection to glaucoma patients receiving standard-of-care IOP lowering treatment. We propose the following milestone-driven Specific Aims: (1) Optimize AAV2-hAIBP and define AIBP distribution and target engagement in retina; (2) Characterize the in vivo efficacy and non-GLP toxicology of AAV2-hAIBP; and (3) Conduct IND-enabling studies and obtain FDA approval for first-in-human trial. The project will combine expertise and resources from University of California, San Diego, RAFT Pharmaceuticals, and the NIH Blueprint Neurotherapeutics Network – Biologic. Our proposed studies will develop novel gene therapy to reduce retinal neuroinflammation and mitochondrial dysfunction and provide effective neuroprotection to glaucoma patients.

新的证据表明，青光眼是全球失明的主要原因。是发病机制中驱动视网膜神经节细胞（RGC）死亡和视神经变性的关键因素 Toll 样受体 4（TLR4，炎症受体）和 ATP 结合的基因多态性。盒式转运蛋白 A1（ABCA1，细胞胆固醇转运蛋白）与原发性开角症的风险相关我们的研究表明，RGC 和神经胶质细胞中 TLR4 表达增加，ABCA1 表达减少。我们确定了分泌型 apoA-I 结合蛋白（AIBP；基因 APOA1BP）是人类青光眼视网膜的关键。细胞胆固醇代谢的调节因子，通过 ABCA1 依赖性胆固醇控制 TLR4 激活与 ABCA1、AIBP 表达类似，TLR4 占据炎症细胞和活化细胞中的脂筏的消耗。在人类和小鼠青光眼患者中，胆固醇水平和炎症标志物降低，而胆固醇水平和炎症标志物增加 Apoa1bp-/- 小鼠的视力受损，与野生型相比，视网膜 TLR4 增加。和 IL-1β 表达，增强小胶质细胞激活，并增加 RGC 死亡以响应升高的这些发现支持了视网膜中 AIBP 表达恢复的基本原理。在初步研究中，腺相关病毒为青光眼患者提供持续的神经保护。 (AAV)-AIBP 可以保护 RGC 并改善青光眼实验小鼠模型中的视觉功能障碍。此外，重组 AIBP 蛋白可促进线粒体功能并抑制炎症反应培养的穆勒神经胶质细胞和小胶质细胞对升高的静水压的反应基于我们之前和根据这些发现，我们建议开发基于 AAV2-hAIBP 的疗法，以减少视网膜神经炎症和为接受标准护理眼压降低治疗的青光眼患者提供有效的神经保护。提出以下里程碑驱动的具体目标： (1) 优化 AAV2-hAIBP 并定义 AIBP 分布以及视网膜的靶点参与；(2) 表征 AAV2-hAIBP 的体内功效和非 GLP 毒理学； (3) 开展 IND 授权研究并获得 FDA 批准进行首次人体试验。该项目将合并。来自加州大学圣地亚哥分校、RAFT Pharmaceuticals 和 NIH Blueprint 的专业知识和资源神经治疗网络 - 生物。我们提出的研究将开发新的基因疗法来减少视网膜病变。神经炎症和线粒体功能障碍，为青光眼患者提供有效的神经保护。