Key Points
- Researchers are attempting to use focused ultrasound to help deliver anti-inflammatory stem cell exosomes to targeted regions of the brain.
- Focused ultrasound–mediated exosome delivery could open significant new avenues for targeted gene therapy.
In a novel study, a collaborative group of researchers attempted to use nonablative transcranial, low-intensity focused ultrasound (LIFU) without microbubbles to disrupt the blood-brain barrier (BBB). The team sought to investigate the potential of LIFU to precisely deliver therapeutic biological agents (such as exosomes) to specific brain regions without compromising the BBB.
Co-led by Karen Aboody, MD, professor of stem cell biology and regenerative medicine in the Division of Neurosurgery at City of Hope, the results of this research support the use of LIFU as a safe, practical, and affordable technique for improving therapeutic efficacy in inflammatory and degenerative central nervous system (CNS) illnesses. Importantly, targeted drug delivery or gene therapy by LIFU has the potential to significantly improve patient outcomes.
The researchers used a custom-designed, 2-MHz, single transducer LIFU probe (Brainsonix) at a peak pressure of 1.5 MPa in preclinical models. Dextran tracer studies showed that 60 minutes of LIFU was needed to increase BBB permeability, in which they observed adhesion and transcytosis of the tracer across endothelial cells. Next, they labeled stem cell–derived exosomes with Renilla-luciferase (a catalytic enzyme) and intravenously (IV) injected the exosomes immediately after 60 minutes of LIFU to the right hippocampus brain region. This resulted in a significant increase in exosome localization to the right hippocampus, as compared with the left hippocampus or no LIFU.
The team hypothesized that the potential mechanism of LIFU increasing transcytosis of the exosomes could be mechanical, from acoustic radiation forces or a pressure differential across the cellular membranes.
“The use of nonablative LIFU to increase the transport of IV-administered stem cell–derived exosomes across the BBB and enhance localization to targeted brain regions has the potential to significantly augment their therapeutic CNS effects,” said Dr. Aboody. “Exosome therapy may promote suppression of microglial inflammation and survival of endogenous neural progenitors while preventing myelin loss, thus improving brain tissue plasticity and regeneration.”
“This is the first report of exosome delivery to the brain using LIFU,” said Frédéric Padilla, PhD, the Foundation’s Director for the Gene and Cell Therapy Program. “If the technique is further developed and tested, focused ultrasound–mediated exosome delivery could open significant new avenues for gene therapy.”
The research team included scientists from the Regenesis Project, City of Hope, Kimera Laboratories, Drexel University, and the University of California Los Angeles.
See Nature Scientific Reports (Open Access)