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.

青光眼是全球失明的主要原因。新兴证据表明神经胶质神经炎症是驱动视网膜神经节细胞（RGC）死亡和发病机理的视神经变性的关键元素青光眼。 Toll样受体-4（TLR4，炎症受体）和ATP结合中的基因多态性盒式转运蛋白A1（ABCA1，细胞胆固醇转运蛋白）与主要开态的风险有关青光眼。我们的研究表明，TLR4增加并降低RGC和GliA中的ABCA1表达人青光眼视网膜。我们将分泌的ApoA-I结合蛋白（AIBP； Gene apoA1bp）确定为钥匙细胞胆固醇代谢的调节剂，该代谢通过ABCA1依赖性胆固醇控制TLR4激活 TLR4的耗竭在炎症和活化细胞中占据脂质筏。与ABCA1相似，AIBP表达减少了，而人和小鼠青光眼的胆固醇水平和炎症标记有所增加视网膜。 ApoA1bp - / - 小鼠的视力受损，与野生型相比，视网膜TLR4增加了和IL-1β的表达，增强的小胶质细胞激活以及RGC死亡增加，以响应升高眼内压（IOP）。这些发现支持视网膜恢复AIBP表达的理由在青光眼患者中提供持续的神经保护作用。在初步研究中，与腺相关病毒（AAV）-AIBP保护了青光眼实验小鼠模型中的RGC和改善视觉功能障碍。在补充，重组AIBP蛋白促进了线粒体功能以及抑制炎症反应在培养的müller胶质细胞和小胶质细胞中，响应静水压力升高。根据我们以前的和这些发现，我们建议开发基于AAV2-HAIBP的疗法，以减少永久性神经炎症和为接受标准IOP治疗的青光眼患者提供有效的神经保护症。我们提案以下里程碑驱动的特定目的：（1）优化AAV2-HAIBP并定义AIBP分布和目标参与视网膜；（2）表征AAV2-HAIBP的体内效率和非GLP毒理学；（3）进行辅助研究，并获得FDA批准以进行首次人类试验。该项目将结合起来加利福尼亚大学，圣地亚哥大学，筏药和NIH蓝图的专业知识和资源神经疗法网络 - 生物学。我们提出的研究将开发新的基因疗法以减少残留神经炎症和线粒体功能障碍，并为青光眼患者提供有效的神经保护作用。