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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.

用于靶向给药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)是一种破坏性的神经肌肉疾病，可导致进行性肌肉萎缩、自主神经功能障碍和5年内死亡确诊，每年有16,000人被确诊。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展进展，临床前研究表明神经生长因子的潜力神经生长因子(NGF)、胶质源性和神经源性神经营养因子(GDNF和BDNF)，以及有针对性的生物制品，以阻止疾病的进展。然而，临床翻译的治疗肌萎缩侧索硬化症和其他神经系统疾病的治疗方法由于全身给药或短暂性血脑屏障相关并发症损坏。通过使用噬菌体生物扫描策略来执行基于亲和力的筛选，我们的目标是利用类似狂犬病病毒感染的中枢神经系统进入途径来绕过系统传递的障碍和直接针对神经元的靶向治疗。因此，我们建议确定新的靶向多肽和生物制品递送策略来治疗神经系统疾病。通过使用噬菌体生物扫描策略来执行一个基于亲和力的筛选，我们最近发现了一个肽基序，Taxi，它介导肌肉注射后生物活性蛋白的摄取和递送到中枢神经系统注射。在这里，我们演示了CNS靶向肽的能力，以提供一个模型 IP注射后药物进入中枢神经系统。我们建议评估衰老和疾病进展影响向中枢神经系统的靶向药物传递，目标是设计和在肌萎缩侧索硬化症模型中进行临床前试验的合成材料。在这项提案中，我们在出租车的基础上开发共聚材料和人出租车多肽可翻译的CNS递送配方将生物制剂递送到患病的CNS非侵犯性的。