![]() ![]() This has also been used for noninvasive gene delivery to the rodent brain. 6, 7, 17 Use of MRgFUS at lower frequency, in combination with microbubble-mediated cavitation, has been shown to focally open the BBB to facilitate transfer of drugs, 45 antibodies, 18 and nanoparticles 32 from the blood stream to the brain parenchyma. 15, 16, 29 This approach involves focused delivery of ultrasound to a target region, and high-frequency MRgFUS has been used in human patients to create targeted brain lesions to treat essential tremor and pain. One approach that has recently gained increasing interest is MR-guided focused ultrasound (MRgFUS). 10Īn alternative to chemical delivery is mechanical disruption of the BBB. Selective intraarterial delivery of BBB disruption agents could provide more targeted gene delivery and cover larger brain areas, but variability in the vascular supply of various important deep-brain structures creates challenges for reproducible delivery between individuals. ![]() 5, 34, 39, 42 However, systemic administration of mannitol induces widespread opening of the BBB, precluding target-specific gene expression. Use of an osmotic agent such as mannitol has long been known to transiently open the BBB, permitting delivery of a variety of agents to the brain, including viral vectors. To reduce surgical risks and avoid the complexities of direct infusion, noninvasive approaches have been explored to permit intravenous delivery of viral vectors into the brain. Newer approaches have been tested that permit monitoring of contrast spread during infusion as a surrogate for viral vector distribution utilizing specialized catheter systems with intraoperative MRI methodology. Not only does this method carry the attendant risks of invasive surgery, but also efficient distribution of gene therapy agents throughout a target area can be difficult to confirm with traditional infusion methods. Due to the presence of the blood-brain barrier (BBB) and its highly selective permeability, 1, 27 the only current means for efficient delivery of viral vectors to specific regions in the human brain have been through invasive direct injection. ![]() The brain has been a major focus of translational gene therapy research, with several human clinical trials showing safety and evidence of efficacy for Parkinson’s disease, 19, 22, 24, 25 Alzheimer’s disease, 40, 46, 47 and a variety of neurogenetic disorders. G ene therapy has long held promise as a potentially groundbreaking method for improving a variety of complex disorders. ![]()
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