Extracellular Vesicles Released by Genetically Modified Macrophages Activate Autophagy and Produce Potent Neuroprotection in Mouse Model of Lysosomal Storage Disorder, Batten Disease.
Extracellular Vesicles Released by Genetically Modified Macrophages Activate Autophagy and Produce Potent Neuroprotection in Mouse Model of Lysosomal Storage Disorder, Batten Disease.
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DOI：
10.3390/cells12111497
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发表时间：
2023-05-29
期刊：
影响因子：
6
通讯作者：
Batrakova, Elena V.
中科院分区：
文献类型：
--
作者：
El-Hage, Nazira;Haney, Matthew J.;Zhao, Yuling;Rodriguez, Myosotys;Wu, Zhanhong;Liu, Mori;Swain, Carson J.;Yuan, Hong;Batrakova, Elena V.
关键词：
近几十年来，细胞外囊泡（EVs）的应用引起了人们的广泛关注。在此，我们报告了一种新的基于ev的药物递送系统的发展，该系统用于运输溶酶体酶三肽基肽酶-1 （TPP1）来治疗巴顿病（BD）。通过转染tpp1编码pDNA的亲本细胞，实现了巨噬细胞源性ev的内源性负载。单次鞘内注射ev后，在BD小鼠模型中，脑内检测到超过20%的ID/g， ceroid lipofuscinosis neuronal type 2 （CLN2）小鼠。此外，我们还证实了ev在大脑中重复施用的累积效应。负载tpp1的ev （EV-TPP1）具有强大的治疗作用，可有效消除溶酶体中的脂褐素聚集体，减少炎症，提高CLN2小鼠的神经元存活率。在机制方面，EV-TPP1处理导致CLN2小鼠大脑中自噬途径的显著激活，包括自噬相关蛋白LC3和P62的表达改变。我们假设，随着TPP1递送到大脑，以ev为基础的配方可以增强宿主细胞的稳态，通过自噬-溶酶体途径导致脂褐素聚集体的降解。总的来说，继续研究新的和有效的双相障碍治疗方法对于改善受这种疾病影响的人的生活至关重要。
Over the recent decades, the use of extracellular vesicles (EVs) has attracted considerable attention. Herein, we report the development of a novel EV-based drug delivery system for the transport of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1) to treat Batten disease (BD). Endogenous loading of macrophage-derived EVs was achieved through transfection of parent cells with TPP1-encoding pDNA. More than 20% ID/g was detected in the brain following a single intrathecal injection of EVs in a mouse model of BD, ceroid lipofuscinosis neuronal type 2 (CLN2) mice. Furthermore, the cumulative effect of EVs repetitive administrations in the brain was demonstrated. TPP1-loaded EVs (EV-TPP1) produced potent therapeutic effects, resulting in efficient elimination of lipofuscin aggregates in lysosomes, decreased inflammation, and improved neuronal survival in CLN2 mice. In terms of mechanism, EV-TPP1 treatments caused significant activation of the autophagy pathway, including altered expression of the autophagy-related proteins LC3 and P62, in the CLN2 mouse brain. We hypothesized that along with TPP1 delivery to the brain, EV-based formulations can enhance host cellular homeostasis, causing degradation of lipofuscin aggregates through the autophagy–lysosomal pathway. Overall, continued research into new and effective therapies for BD is crucial for improving the lives of those affected by this condition.
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影响因子：
3
作者：
Kadar, Andrea;Wittmann, Gabor;Liposits, Zsolt;Fekete, Csaba
通讯作者：
Fekete, Csaba
DOI：
10.1016/j.jconrel.2015.07.030
发表时间：
2015-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Batrakova EV;Kim MS
通讯作者：
Kim MS
DOI：
10.3390/molecules26113161
发表时间：
2021-05-25
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Dąbrowska M;Souto EB;Nowak I
通讯作者：
Nowak I
外泌体作为帕金森氏病疗法的药物。
DOI：
10.1016/j.jconrel.2015.03.033
发表时间：
2015-06-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Haney MJ;Klyachko NL;Zhao Y;Gupta R;Plotnikova EG;He Z;Patel T;Piroyan A;Sokolsky M;Kabanov AV;Batrakova EV
通讯作者：
Batrakova EV
影响因子：
9.3
作者：
Domowicz MS;Chan WC;Claudio-Vázquez P;Gonzalez T;Schwartz NB
通讯作者：
Schwartz NB