摘要
目的:本研究旨在探索一种非侵略性基于单核细胞能够将治疗性的基因传送到发病性脑部的传递系统的潜在价值。通过首先建立慢病毒载体(LV)介导的基因转移到新鲜分离的单核细胞中的优化条件,随后在小鼠模型中研究发炎的脑归巢效率和通过载体单核细胞的体内细胞介导的转基因表达,进行研究急性亚区域性神经炎症。 材料和方法:使用新优化的自旋感染方法,高达35%的新鲜分离的单核细胞被成功地转导与LV系统DHIV-101在M.O.I。同时,在静脉内(IV)施用新鲜分离的单核细胞后,在高密度发炎的脑区域中检测到细胞运输和积累,证实了使用单核细胞作为靶向脑的细胞载体的适合性。然而,LV转导的单核细胞(TD-MO)显示显着降低的归巢效率进入脑,可能是由于LV转导后的初始不健康的细胞状态。尽管通过PCR确认了转基因在脑中的存在,但是通过RT-PCR或ELISA在炎症性中枢神经系统(CNS)位点内未检测到转基因表达。相反,在脾脏中检测到高密度的功能性TD-MO及其转基因产物。 结论:总之,这项研究表明IV输注单核细胞能够迁移到大脑,并保持活力和功能的体内后LV转导,保证更深入的研究,以充分建立条件,以减少由载体诱导的细胞毒性转导,从而增强载体单核细胞的脑归巢效率。
关键词: 单核细胞、非侵入性递送、基于细胞的传递系统、基因治疗、大脑、神经炎症
Current Gene Therapy
Title:Evaluation on Monocyte-Mediated Delivery of a Therapeutic Gene into the Inflamed Brain
Volume: 16 Issue: 6
关键词: 单核细胞、非侵入性递送、基于细胞的传递系统、基因治疗、大脑、神经炎症
摘要: Objective: This study was aimed to explore the potential of a non-invasive monocytes-based delivery system to transport therapeutic genes into the diseased brain. The study was conducted by first establishing the optimized conditions for lentiviral vector (LV)-mediated gene transfer into freshly isolated monocytes, followed by investigating the inflamed-brain homing efficiency and in vivo cell-mediated transgene expression by carrier monocytes in a mouse model with acute sub-regional neuroinflammation. Materials & Methods: Using a newly optimized spin-infection method, up to 35% of freshly isolated monocytes were successfully transduced with the LV system DHIV-101 at M.O.I. of 10. Meanwhile, cell trafficking and accumulation were detected in the inflamed brain regions in high density following intravenous (IV) administration of freshly isolated monocytes, confirming the suitability of using monocytes as cellular vehicles targeting the brain. However, LV transduced monocytes (TD-MO) displayed significantly reduced homing efficiency into the brain, possibly due to the initial unhealthy cellular states following LV transduction. Although the presence of transgene in the brain was confirmed by PCR, transgene expression was not detected within the inflammatory central nervous system (CNS) sites by RT-PCR or ELISA. Instead, high density of functional TD-MO and their transgene products were detected in the spleen. Conclusion: In conclusion, this study demonstrated that IV-infused monocytes were able to migrate into the brain, and remain viable and functional in vivo following LV transduction, warranting more indepth research to fully establish the conditions in order to reduce cellular toxicity induced by vector transduction, and thus enhance the brain homing efficiency of carrier monocytes.
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Evaluation on Monocyte-Mediated Delivery of a Therapeutic Gene into the Inflamed Brain, Current Gene Therapy 2016; 16 (6) . https://dx.doi.org/10.2174/1566523217666161118165710
DOI https://dx.doi.org/10.2174/1566523217666161118165710 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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