期刊
PHARMACEUTICS
卷 13, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics13081245
关键词
gene therapy; AAV9; focused ultrasound; blood-brain barrier; microbubbles
资金
- Inserm, Aix Marseille University
- AFM-Telethon (Strategic pole MNH Decrypt)
- Promex Stiftung Fur Die Forschung
- Rettsyndrome.org
- Association Francaise du Syndrome de Rett (AFSR)
- ANR DROPMUT [ANR-19-CE19-0011]
- plan cancer project GRAVITY [PC201613]
Gene therapy is a powerful tool for treating diseased tissues and providing lasting and effective correction. The combination of focused ultrasound and microbubbles appears to be a technological breakthrough for delivering therapeutic agents to the central nervous system.
Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS. While most studies focus on a specific targeted area of the brain, the present work proposes to permeabilize the entire brain for gene therapy in several pathologies. Our results show that, after i.v. administration and FUS sonication in a raster scan manner, a self-complementary AAV9-CMV-GFP vector strongly and safely infected the whole brain of mice. An increase in vector DNA (19.8 times), GFP mRNA (16.4 times), and GFP protein levels (17.4 times) was measured in whole brain extracts of FUS-treated GFP injected mice compared to non-FUS GFP injected mice. In addition to this increase in GFP levels, on average, a 7.3-fold increase of infected cells in the cortex, hippocampus, and striatum was observed. No side effects were detected in the brain of treated mice. The combining of FUS and AAV-based gene delivery represents a significant improvement in the treatment of neurological genetic diseases.
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