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

用于靶向药物递送以治疗的多聚体肽共聚物制剂 神经系统疾病 肌萎缩侧索硬化症（ALS）是一种毁灭性的神经肌肉疾病， 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。研究表明， 在理解疾病背后的细胞机制方面取得了巨大的进步 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 有针对性的生物制剂，以阻止疾病的进展。然而，临床翻译的 治疗ALS和其他神经系统疾病的疗法已经落后， 与全身给药或一过性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进行基于亲和力的生物淘选， 筛选，我们的目标是利用类似于狂犬病病毒感染的CNS进入途径， 绕过全身递送的障碍并将治疗剂直接靶向神经元。 因此，我们建议鉴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 在基于亲和力的筛选中，我们最近发现了一个肽基序TAxI，它介导 肌内注射后生物活性蛋白质的摄取和递送至CNS 注射在这里，我们证明了中枢神经系统靶向肽的能力，提供一个模型， IP注射后药物进入CNS。我们建议评估衰老和疾病 进展影响靶向药物递送至CNS，目的是设计和 合成用于ALS模型中的临床前测试的材料。在本提案中，我们 通过开发共聚物材料和人TAxI-肽， 将生物制剂递送到患病的CNS中的可翻译的CNS递送制剂 侵入性地

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.