Nanoformulation of the BDNF for treatment of stroke

描述（由申请人提供）：本项目开发了一种将脑源性神经营养因子（BDNF）递送至中枢神经系统的制剂，并评价了使用该制剂治疗缺血性卒中的候选药物。脑源性神经营养因子在中风后有神经保护和神经变性的作用。然而，使用天然BDNF作为全身给药的治疗剂受到其不良脑积累的阻碍。为了解决这个问题，我们提出了一种新的但简单的和可扩展的聚合物的BDNF纳米制剂，纳米BDNF，其中BDNF被纳入到安全和生物相容性的聚（乙二醇）-聚（L-谷氨酸）（PEG-PGA）嵌段共聚物的聚离子复合物。当天然BDNF与PEG-PGA嵌段共聚物混合时，在温和的水性条件下自发地产生复合物，PEG-PGA嵌段共聚物将BDNF分子捕获在纳米级尺寸（<100 nm）的核-壳颗粒中。初步研究表明，nano-BDNF将大大提高脑内BDNF的摄取，并增加BDNF治疗的疗效，以引起脑卒中后的神经保护和神经修复。我们建议将纳米BDNF作为一种潜在的治疗剂，用于治疗中风动物模型中的脑损伤。这将通过以下方式实现：（1）内部生产大量的人重组BDNF，并开发具有优化组成的纳米BDNF的简单、可扩展和稳健的程序;（2）确定静脉内给药后纳米BDNF的脑药代动力学，并确定用于功效研究的最佳组成;和（3）测定纳米BDNF治疗对缺血/再灌注诱导的小鼠大脑中动脉闭塞（MCAO）模型中慢性恢复的治疗效果。我们使用逐步过程;每一步都有自己的通过/不通过标准，以确定将被推进临床前开发的主要纳米BDNF候选物。后续治疗开发计划将实施产品开发步骤，并导致IND备案。

DESCRIPTION (provided by applicant): This project develops a formulation for the delivery of the brain-derived neurotrophic factor (BDNF) to the central nervous system and evaluates the drug candidate using this formulation for the treatment of ischemic stroke. BDNF has shown potential to exert neuroprotective and neurodegenerative effects when administered after stroke. However, the use of native BDNF as therapeutic agent for systemic administration is hindered by its poor brain accumulation. To address this problem we propose a novel yet simple and scalable polymeric nano-formulation of BDNF, nano-BDNF, in which BDNF is incorporated into polyion complexes with safe and biocompatible poly (ethylene glycol)-poly (L-glutamate) (PEG-PGA) block copolymer. The complexes are produced spontaneously in mild aqueous conditions upon mixing of native BDNF with the PEG-PGA block copolymer, which entraps the BDNF molecule in nanoscale size (<100 nm) core-shell particles. Preliminary studies suggest that nano-BDNF will strongly improve the brain uptake of BDNF and increase efficacy of BDNF treatment to elicit neuroprotection and neuro-restoration after stroke. We propose to advance nano-BDNF as a potential therapeutic agent for the treatment of brain injury in an animal model of stroke. This will be achieved by (1) producing in house the abundant amount of human recombinant BDNF and developing simple, scalable and robust procedure for nano-BDNF with optimized composition; (2) determining the brain pharmacokinetics of nano-BDNF after intravenous administration and identifying the best composition for efficacy studies; and (3) determining the therapeutic effect of nano-BDNF treatment on chronic recovery in an ischemia/reperfusion- induced mouse middle cerebral artery occlusion (MCAO) model. We use step-wise process; each step has its own go/no go criteria to identify a lead nano-BDNF candidate that will be taken forward into preclinical development. The plan for subsequent therapy development will implement the product development steps and result in the filing of IND.