Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound
Open accessAbstract
OBJECTIVE: Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain. METHODS: Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses. RESULTS: Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%–75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons. CONCLUSIONS: This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders.
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AAV1, AAV2, or chimeric AAV1/2 vectors, which showed low BBB-crossing per se, successfully penetrated into directed brain regions after FUS-MB treatment.
“It was reported that IV infusion of AAV1, AAV2 or chimeric AAV1/2 vector, which showed low BBB-crossing per se, successfully penetrated into directed brain regions after FUS-MB treatment [140–142].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [141]
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- Authors
- Stavarache, M. A., Petersen, N., Jurgens, E. M., Milstein, E. R., Rosenfeld, Z. B., Ballon, D. J., & Kaplitt, M. G.
- Affiliations
- Laboratory of Molecular Neurosurgery, Department of Neurological Surgery, and
- Citigroup (US)
- Venue
- Journal of Neurosurgery
- Published
- 2019-03
- Volume
- 130
- Issue
- 3
- Pages
- 989-998
- ISSN
- 0022-3085 (ISSN-L)
- 1933-0693
- OpenAlex
- W2801229775
- Cited by
- 76
- References
- 50
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 11 · 2021: 13 · 2020: 16 · 2019: 9 · 2018: 1
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of neurosurgery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- JPB Foundation
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- MR-guided focused ultrasound, blood-brain barrier disruption, adeno-associated virus vectors, striatum, microbubbles, transduction efficiency, neuroinflammation, neurotoxicity, neurological disorders
- MeSH terms
- Dependovirus, Animals, Brain, Genetic Vectors, Image Processing, Computer-Assisted, Immunohistochemistry, Inflammation, Magnetic Resonance Imaging, Male, Nervous System Diseases, Ultrasonography, Genetic Therapy, Blood-Air Barrier, Rats, Sprague-Dawley, Gene Transfer Techniques, Transgenes, Green Fluorescent Proteins, Rats
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