Targeting Ligands for autonomic uptake and drug delivery to the brain and spinal cord

项目摘要 在世界范围内，超过4000万人被诊断患有神经退行性疾病，如 肌萎缩侧索硬化症（ALS）、帕金森病或阿尔茨海默病。然而，每年的成本- 护理超过2260亿美元，尚未开发出有效的药物和交付策略来治疗 这些疾病。该项目的总体目标是开发针对吸收和交付的技术， 自主神经系统，生物制剂（如蛋白质，肽，或核酸药物）的中枢 神经系统（CNS）。由于血脑屏障（BBB）和血脊髓屏障（BSCB）保护了脑细胞， CNS从药物递送，这些神经退行性疾病的潜在疗法尚未实现， 部分原因是缺乏交付技术。我们的方法基于病毒能够 靶向外周神经元以促进摄取和逆行转运到CNS中。我们将筛选一个 重组噬菌体展示文库，用于腹膜内（IP）后摄取和递送至脑和脊髓 注射下一代DNA测序（NGS）分析将用于分析组织中的高频率 这些克隆可以运输到中枢神经系统。我们假设，将体内噬菌体展示屏幕与NGS偶联， 能够对共有序列进行经验性的高通量分析，以工程化靶向配体用于递送 到CNS。在这项工作中，我们将优化肽配体，并评估这些肽在体内的能力， 增强IP注射后蛋白质-药物在脑和脊髓中的积聚。

Project Summary Worldwide, over 40 million people have been diagnosed with a neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS), Parkinson's Disease, or Alzheimer's Disease. Yet, with an annual cost-of- care greater than $226 billion, there have yet to be effective drugs and delivery strategies developed to treat these diseases. The overall goal of this project is to develop technologies that target uptake and delivery, via the autonomic nervous system, of biologics (e.g. proteins, peptides, or nucleic acid drugs) to the central nervous system (CNS). Since the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) protect the CNS from drug-delivery, potential therapies for these neurodegenerative diseases have not been realized, in part, due to the lack of delivery technologies. We base our approach on the knowledge that viruses are able to target neurons in the periphery to facilitate uptake and retrograde transport into the CNS. We will screen a recombinant phage display library for uptake and delivery to the brain and spinal cord after intraperitoneal (IP) injection. Next-generation DNA sequencing (NGS) analysis will be used to analyze tissues for high-frequency clones that transport into the CNS. We hypothesize that coupling an in vivo phage display screen with NGS will enable an empiric, high-throughput analysis of consensus sequences to engineer a targeting ligand for delivery to the CNS. In this work, we will optimize peptide ligands and evaluate these peptides in vivo for their ability to enhance protein-drug accumulation in the brain and spinal cord after IP injection.