Focused-ultrasound Mediated Anti-Alpha-Synuclein Antibody Delivery for the Treatment of Parkinson's Disease

摘要

Focused ultrasound (FUS) in conjunction with microbubbles is a technique to achieve noninvasive, transient, and localized blood-brain barrier (BBB) opening to enhance drug delivery to the brain. Here we explored the potential of FUS-mediated delivery of anti-alpha synuclein (a-syn) monoclonal antibodies (mAb) for the treatment of Parkinson's disease. Transgenic A53T mice that express the human A53T a-syn at 6-7 months of age received 3 weekly sonications followed by one-month survival. Monoclonal anti-a-syn antibodies ([MJFR1], Abcam) were mixed with in-house manufactured size-isolated microbubbles (4-5 μm) and intravenously injected before FUS sonications. Mice were sonicated using a single-element FUS transducer (center frequency 1.5 MHz) with the following acoustic parameters: peak-negative pressure 0.45 MPa, pulse length 6.7 ms, pulse repetition frequency 5 Hz, and duration of 60 s. Quantification using a minimum error thresholding technique demonstrated reduced a-syn load in mice treated with both FUS and antibody, without significant change in neuronal cell count. Reduction of a-syn aggregation was present primarily in the midbrain in both hemispheres of treated brain, but with a higher reduction in the FUS-treated hemisphere. These findings suggest that weekly treatments with FUS and anti-a-syn antibodies could successfully reduce a-syn burden in transgenic mouse models of PD.