期刊
JOURNAL OF EXTRACELLULAR VESICLES
卷 10, 期 5, 页码 -出版社
WILEY
DOI: 10.1002/jev2.12058
关键词
alpha-galactosidase A; drug delivery; enzyme replacement therapy; Fabry disease; lysosomal storage disorders; N-sulfoglucosamine sulfohydrolase; Sanfilippo syndrome
类别
资金
- ISCIII (Fondo Europeo de Desarrollo Regional (FEDER)) [PI18_00871]
- CIBER-BBN (EXPLORE)
The study revealed that using extracellular vesicles as carriers for therapeutic enzymes is an effective method to enhance protein activity and efficacy, particularly in restoring cellular function in lysosomal storage disorders.
In the present study the use of extracellular vesicles (EVs) as vehicles for therapeutic enzymes in lysosomal storage disorders was explored. EVs were isolated from mammalian cells overexpressing alpha-galactosidase A (GLA) or N-sulfoglucosamine sulfohydrolase (SGSH) enzymes, defective in Fabry and Sanfilippo A diseases, respectively. Direct purification of EVs from cell supernatants was found to be a simple and efficient method to obtain highly active GLA and SGSH proteins, even after EN lyophilization. Likewise, EVs carrying GLA (EV-GLA) were rapidly uptaken and reached the lysosomes in cellular models of Fabry disease, restoring lysosomal functionality much more efficiently than the recombinant enzyme in clinical use. In vivo, EVs were well tolerated and distributed among all main organs, including the brain. DiR-labelled EVs were localized in brain parenchyma 1 h after intra-arterial (internal carotid artery) or intravenous (tail vein) administrations. Moreover, a single intravenous administration of EV-GLA was able to reduce globotriaosylceramide (Gb3) substrate levels in clinically relevant tissues, such kidneys and brain. Overall, our results demonstrate that EVs from cells overexpressing lysosomal enzymes act as natural protein delivery systems, improving the activity and the efficacy of the recombinant proteins and facilitating their access to organs neglected by conventional enzyme replacement therapies.
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