Targeted Delivery of Self-Complementary Adeno-Associated Virus Serotype 9 to the Brain, Using Magnetic Resonance Imaging-Guided Focused Ultrasound

Abstract

Noninvasive drug delivery to the brain remains a major challenge for the treatment of neurological disorders. Transcranial focused ultrasound combined with lipid-coated gas microspheres injected into the bloodstream has been shown to increase the permeability of the blood-brain barrier locally and transiently. Coupled with magnetic resonance imaging, ultrasound can be guided to allow therapeutics administered in the blood to reach brain regions of interest. Using this approach, we perform gene transfer from the blood to specific regions of the mouse brain. Focused ultrasound was targeted to the right hemisphere, at multiple foci, or restricted to one focal point of the hippocampus or the striatum. Doses from 5 × 10(8) to 1.25 × 10(10) vector genomes per gram (VG/g) of self-complementary adeno-associated virus serotype 9 carrying the green fluorescent protein were injected into the tail vein. A dose of 2.5 × 10(9) VG/g was optimal to express the transgene, 12 days later, in neurons, astrocytes, and oligodendrocytes in brain regions targeted with ultrasound, while minimizing the infection of peripheral organs. In the hippocampus and striatum, predominantly neurons and astrocytes were infected, respectively. Transcranial focused ultrasound applications could fulfill a long-term goal of gene therapy: delivering vectors to diseased brain areas directly from the circulation, in a noninvasive manner.

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

“…FUS-BBBO combines transcranial ultrasound in the low-intensity regime with systemically administered microbubbles, whose stable cavitation in blood vessels at the ultrasound focus results in localized, temporary and reversible opening of the BBB 12,13 . This allows small molecules, proteins, nanoparticles or viral capsids 12,[14][15][16][17] to enter the brain at the site of applied ultrasound. FUS-BBBO has been used in multiple animal species 12,18,19 , and is currently undergoing clinical testing 9 .…”

Intracranial Applications of Magnetic Resonance-guided Focused Ultrasound

“…Notably, antibody concentrations in the brain were similar to those achieved with surgical transplantation, as well as with intravenous infusion, but with 10 times less the dose. The same group also demonstrated the successful translocation of significant concentrations of neural stem cells, as well as adenoassociated virus type 9, into the brain using MRgFUS BBB disruption [72,73]. These promising findings suggest that MRgFUS may offer a gateway into the brain for previously impassable compounds.…”

A review of potential applications of MR-guided focused ultrasound for targeting brain tumor therapy

“…53 For example, MRgFUS delivered intravenous methotrexate to the brains of healthy rabbits at concentrations 13 times higher than intravenous methotrexate delivery alone (p < 0.01) and more than 3 times higher than methotrexate delivery via the internal carotid artery without MRgFUS (p < 0.01). 40 Thus, MRgFUS can reduce side effects of chemotherapeutic agents by requiring a lower systemic dose to reach a desired brain tumor tissue concentration.…”