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.
The brain-derived neurotrophic factor (BDNF) has promise to ameliorate stroke but its use as therapeutic agent for treatment stroke in humans is drastically hindered by poor penetration of native BDNF to the brain. We propose novel biocompatible nano-formulation of BDNF, which has shown to increase brain delivery of active BDNF and enhance its beneficial effect on post stroke neurological recovery in animal models. The proposal will identify the lead drug candidate that will be taken forward into further preclinical development.
|Jiang, Yuhang; Fay, James M; Poon, Chi-Duen et al. (2018) Nanoformulation of Brain-Derived Neurotrophic Factor with Target Receptor-Triggered-Release in the Central Nervous System. Adv Funct Mater 28:|
|Yuan, Dongfen; Zhao, Yuling; Banks, William A et al. (2017) Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials 142:1-12|
|Harris, Nia M; Ritzel, Rodney; Mancini, Nickolas S et al. (2016) Nano-particle delivery of brain derived neurotrophic factor after focal cerebral ischemia reduces tissue injury and enhances behavioral recovery. Pharmacol Biochem Behav 150-151:48-56|