Multimeric Peptide Copolymer Formulations for Targeted Drug Delivery to Treat Nervous System Disorders

用于治疗神经系统疾病的靶向药物递送的多聚肽共聚物制剂

基本信息

批准号：
10178139
负责人：
Drew L Sellers
金额：
$ 36.54万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10178139
关键词：
Affinity Age Aging Amino Acid Substitution Amino Acids Amyotrophic Lateral Sclerosis Antibodies Autonomic Dysfunction Autonomic nervous system Avidin Avidity Bacteriophages Binding Binding Proteins Biodistribution Biological Biological Availability Biological Products Blood Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Catalogs Cells Central Nervous System Agents Central Nervous System Diseases Cessation of life Clinic Coupled Custom Cyclization Data Development Diagnosis Digestion Disease Disease Progression Dose Drug Delivery Systems Drug Modelings Drug Targeting Endothelium Engineering Equus caballus Formulation Gel Goals Histologic Human In Vitro Individual Intramuscular Injections Intraperitoneal Injections Ligands Mass Spectrum Analysis Mediating Metabolism Methodology Methods Modeling Modification Monitor Motor Neurons Mus Muscular Atrophy Nerve Degeneration Nerve Growth Factors Neuraxis Neuromuscular Diseases Neurons Organ Pathway interactions Patients Penetrance Peptide Hydrolases Peptide Synthesis Peptides Peripheral Pharmaceutical Preparations Preclinical Testing Primary Lateral Sclerosis Proteins Rabies virus Research Resistance Serum Spinal Cord Structure Therapeutic Tissues Toxic effect Translating Translations United States Virus Diseases aged amyotrophic lateral sclerosis therapy base blood-brain barrier disruption clinical translation copolymer design glial cell-line derived neurotrophic factor improved in vivo induced pluripotent stem cell lipophilicity macromolecule mouse model nervous system disorder neurotrophic factor new technology next generation sequencing non-invasive system novel novel therapeutics peptide structure polymerization pre-clinical research premature receptor receptor binding relating to nervous system scaffold sciatic nerve side effect success targeted delivery targeted treatment therapeutic development therapeutically effective transcytosis uptake

项目摘要

Multimeric Peptide Copolymer Formulations for Targeted Drug Delivery to Treat Nervous System Disorders Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease that leads to progressive muscle wasting, autonomic dysfunction and death within 5 years of diagnosis, and each year >16,000 people are diagnosed. As research has made tremendous strides in understanding the cellular mechanisms that underlie disease progression, pre-clinical research has demonstrated the potential of nerve growth factor (NGF), glial derived and neural derived neurotrophic factor (GDNF and BDNF), and targeted biologics to halt disease progression. However, the clinical translation of therapeutics to treat ALS and other nervous system disorders has lagged due to complications associated with systemic administration or transient blood-brain barrier damage. By using a bacteriophage biopanning strategy to perform an affinity based screen, we aim to exploit a CNS entry pathway similar to rabies virus infection to circumvent the barriers of systemic delivery and target therapeutics to neurons directly. Thus, we propose to identify novel targeting peptides and biologics delivery strategies to treat nervous system diseases. By using a bacteriophage biopanning strategy to perform an affinity based screen, we have recently identified a peptide motif, TAxI, that mediates uptake and delivery of a biologically active protein to the CNS after intramuscular injection. Here, we demonstrate the ability of CNS targeting-peptides to deliver a model drug into the CNS after IP injection. We propose to evaluate how aging and disease progression impacts targeted drug delivery to the CNS with the goal of designing and synthesizing materials for pre-clinical testing in a model of ALS. In this proposal, we build upon TAxI by developing copolymer materials and a human TAxI-peptide for translatable CNS delivery formulations to deliver biologics into the diseased CNS non- invasively.

用于靶向药物递送治疗的多聚肽共聚物制剂神经系统疾病肌萎缩侧索硬化症 (ALS) 是一种破坏性神经肌肉疾病，会导致进行性肌肉萎缩、自主神经功能障碍和 5 年内死亡诊断，每年有超过 16,000 人被诊断。正如研究所做的那样在理解疾病背后的细胞机制方面取得了巨大进步进展，临床前研究已经证明了神经生长因子的潜力 (NGF)、胶质源性和神经源性神经营养因子（GDNF 和 BDNF），以及靶向生物制剂来阻止疾病进展。然而，临床转化由于以下原因，治疗 ALS 和其他神经系统疾病的疗法已经滞后与全身给药或短暂血脑屏障相关的并发症损害。通过使用噬菌体生物淘选策略来执行基于亲和力的筛选，我们的目标是利用类似于狂犬病病毒感染的中枢神经系统进入途径绕过全身递送的障碍并将治疗直接靶向神经元。因此，我们建议确定新的靶向肽和生物制剂递送策略治疗神经系统疾病。通过使用噬菌体生物淘选策略来执行基于亲和力的筛选，我们最近鉴定了一个肽基序 TAxI，它介导肌内注射后，生物活性蛋白被摄取并输送至中枢神经系统注射。在这里，我们展示了 CNS 靶向肽提供模型的能力腹腔注射后药物进入中枢神经系统。我们建议评估衰老和疾病如何进展影响中枢神经系统的靶向药物输送，目的是设计和在 ALS 模型中合成用于临床前测试的材料。在这个提案中，我们通过开发共聚物材料和人类 TAxI 肽，以 TAxI 为基础可翻译的中枢神经系统递送制剂，将生物制剂递送到患病的中枢神经系统中侵入性地。