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

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。

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.