神经药理学报

神经药理学报 ›› 2018, Vol. 8 ›› Issue (4): 32-34.

• Session 1B: Novel Targets and Approaches in the CNS • 上一篇    下一篇

Macrophage Gene Therapy in the Central Nervous System

So Yoon Lee1，Cara Orji1，2，ZHANG Zi-jian 1，ZHANG Hao-yun 1，3，Anthony Bastian1，2，Adriana Galvez1，2，DOU
Huan-yu 1，2   

  1. 1.　 Department of Biomedical Sciences，Paul L. Foster School of Medicine
    2.　 Gradulate School of Biomedical Sciences，Texas Tech University Health Sciences Center，El Paso，Texas,79905，USA
    3.　 Weifang Medical University，Shandong，China
  • 出版日期:2018-08-26 发布日期:2018-11-16

Macrophage Gene Therapy in the Central Nervous System

So Yoon Lee1，Cara Orji1，2，ZHANG Zi-jian 1，ZHANG Hao-yun 1，3，Anthony Bastian1，2，Adriana Galvez1，2，DOU
Huan-yu 1，2   

  1. 1.　 Department of Biomedical Sciences，Paul L. Foster School of Medicine
    2.　 Gradulate School of Biomedical Sciences，Texas Tech University Health Sciences Center，El Paso，Texas,79905，USA
    3.　 Weifang Medical University，Shandong，China
  • Online:2018-08-26 Published:2018-11-16

摘要： Regulation of immune responses is particular important in recovery after stroke, traumatic brain injury, and brain infections by inhibiting inflammation and reinstating rescue environment. Gene delivery based immunotherapy appears to have significant therapeutic potential for the treatment of neurological conditions by inhibition of neuroinflammation to prevent irreversible destructive mechanisms. However, current gene delivery systems lack desired convenience, efficiency, and safety. Nanocarriers offers an   attractive gene delivery system that overcome the immunogenic and long-term oncologic effects of the viral vectors. Using branched PEI lipids with PLGA, we developed a highly efficient core-shell nanoparticle (NP) gene delivery system. These IL-4 plasmid DNA (pIL-4) loaded NPs (pIL-4-NPs) were effectively delivered pIL-4 to the human blood monocytes derived macrophages (MDM) and mouse bone marrow-derived macrophages (BMM). Furthermore, pIL-4-NPs quickly escaped lysosomes and entered the nuclei of these cells. In in vitro transfection assays, the pIL-4-NPs had higher transfection efficiency, in contrast, PEI25KPEI liposomes and PLGA NPs were unable to transfect MDM and BMM. In LPS-induced inflammatory in vitro and in vivo models, transfection of pIL-4-NPs decreased LPS-induced pro-inflammatory cytokines, such as IL-1, IL6, and TNF-?. Our findings indicate that pIL-4-NPs delivery system is capable of effectively deliver IL-4 plasmid DNA into human and murine macrophages, which consistently express IL-4 in vitro and in vivo. The pIL-4-NPs dramatically diminished pro-inflammatory cytokines expression, exhibited anti-neuroinflammatory and neuroprotective efficacy when macrophages were activated by LPS. Thus, branched PEI lipids and PLGA formed core-shell NPs are a promising gene delivery platform for immunotherapy in neurological ailments.

Abstract: Regulation of immune responses is particular important in recovery after stroke, traumatic brain injury, and brain infections by inhibiting inflammation and reinstating rescue environment. Gene delivery based immunotherapy appears to have significant therapeutic potential for the treatment of neurological conditions by inhibition of neuroinflammation to prevent irreversible destructive mechanisms. However, current gene delivery systems lack desired convenience, efficiency, and safety. Nanocarriers offers an   attractive gene delivery system that overcome the immunogenic and long-term oncologic effects of the viral vectors. Using branched PEI lipids with PLGA, we developed a highly efficient core-shell nanoparticle (NP) gene delivery system. These IL-4 plasmid DNA (pIL-4) loaded NPs (pIL-4-NPs) were effectively delivered pIL-4 to the human blood monocytes derived macrophages (MDM) and mouse bone marrow-derived macrophages (BMM). Furthermore, pIL-4-NPs quickly escaped lysosomes and entered the nuclei of these cells. In in vitro transfection assays, the pIL-4-NPs had higher transfection efficiency, in contrast, PEI25KPEI liposomes and PLGA NPs were unable to transfect MDM and BMM. In LPS-induced inflammatory in vitro and in vivo models, transfection of pIL-4-NPs decreased LPS-induced pro-inflammatory cytokines, such as IL-1, IL6, and TNF-?. Our findings indicate that pIL-4-NPs delivery system is capable of effectively deliver IL-4 plasmid DNA into human and murine macrophages, which consistently express IL-4 in vitro and in vivo. The pIL-4-NPs dramatically diminished pro-inflammatory cytokines expression, exhibited anti-neuroinflammatory and neuroprotective efficacy when macrophages were activated by LPS. Thus, branched PEI lipids and PLGA formed core-shell NPs are a promising gene delivery platform for immunotherapy in neurological ailments.