BACKGROUND: Neurological disorders are the second leading cause of death and the leading cause of disability in the world. Thus, the development of novel disease-modifying strategies is clearly warranted. We have previously developed a therapeutic approach using mouse targeted rabies virus glycoprotein (RVG) extracellular vesicles (EVs) to deliver minicircles (MCs) expressing shRNA (shRNA-MCs) to induce long-term α-synuclein down-regulation. Although the previous therapy successfully reduced the pathology, the clinical translation was extremely unlikely since they were mouse extracellular vesicles. METHODS: To overcome this limitation, we developed a source of human RVG-EVs compatible with a personalized therapy using immature dendritic cells. Human peripheral blood monocytes were differentiated in vitro into immature dendritic cells, which were transfected to express the RVG peptide. RVG-EVs containing shRNA-MCs, loaded by electroporation, were injected intravenously in the α-synuclein performed fibril (PFF) mouse model. Level of α-synuclein, phosphorylated α-synuclein aggregates, dopaminergic neurons and motor function were evaluated 90 days after the treatment. To confirm that EVs derived from patients were suitable as a vehicle, proteomic analysis of EVs derived from control, initial and advanced Parkinson's disease was performed. RESULTS: The shRNA-MCs could be successfully loaded into human RVG-EVs and downregulate α-synuclein in SH-SY5Y cells. Intravenous injection of the shRNA-MC-loaded RVG-EVs induced long-term downregulation of α-synuclein mRNA expression and protein level, decreased α-synuclein aggregates, prevented dopaminergic cell death and ameliorated motor impairment in the α-synuclein PFF mouse model. Moreover, we confirmed that the EVs from PD patients are suitable as a personalized therapeutic vehicle. CONCLUSION: Our study confirmed the therapeutic potential of shRNA-MCs delivered by human RVG-EVs for long-term treatment of neurodegenerative diseases. These results pave the way for clinical use of this approach.
Development of human targeted extracellular vesicles loaded with shRNA minicircles to prevent parkinsonian pathology.
阅读:7
作者:Izco Maria, Sola Carlos, Schleef Martin, Schmeer Marco, de Toro MarÃa, Verona Guglielmo, Carlos Estefania, Reinares-Sebastian Alejandro, Colina Sandra, Marzo-Sola Maria Eugenia, Garcia-Sanmartin Josune, Fernández-Irigoyen JoaquÃn, SantamarÃa Enrique, Mugica-Vidal Rodolfo, Blesa Javier, Alvarez-Erviti Lydia
期刊: | Translational Neurodegeneration | 影响因子: | 15.200 |
时间: | 2025 | 起止号: | 2025 May 26;14(1):26 |
doi: | 10.1186/s40035-025-00484-7 |
特别声明
1、本文转载旨在传播信息,不代表本网站观点,亦不对其内容的真实性承担责任。
2、其他媒体、网站或个人若从本网站转载使用,必须保留本网站注明的“来源”,并自行承担包括版权在内的相关法律责任。
3、如作者不希望本文被转载,或需洽谈转载稿费等事宜,请及时与本网站联系。
4、此外,如需投稿,也可通过邮箱info@biocloudy.com与我们取得联系。