Intersections of neuromodulation, focused ultrasound, and gene delivery with brain-penetrating nanoparticles

Abstract

Focused ultrasound (FUS) can modulate CNS tissue function by facilitating MR image-guided transfection of selected brain structures with therapeutic genes. Conversely, we hypothesize that modulation of CNS tissue with FUS may be used to enhance transfection. In previous studies, our group has (i) transfected selected brain structures by delivering systemically administered, non-viral, “brain-penetrating” nanoparticles (BPN) across the blood-brain barrier (BBB) with FUS and microbubbles (MBs) and (ii) employed this platform to restore dopaminergic motor neuron structure and function in a rat Parkinson’s disease model via delivery of a neurotrophic factor (GDNF) gene to striatum. Here, we show that pre-conditioning of rat neural tissue with pulsed FUS or pulsed FUS + MBs before intrastriatal convection-enhanced delivery of BPN complexed with a reporter gene (CMV-ZsGreen) serves to enhance transfection volume by 36% or 151%, respectively. Pre-conditioning with both FUS and FUS + MBs proved effective in mice as well, with both FUS protocols yielding ~75% increases in transfection. We conclude that modulation of CNS tissue plays an important role in dispersing BPN after they are delivered across the BBB using pulsed FUS and MBs. Pre-conditioning of CNS tissue with FUS may eventually represent an attractive means for enhancing transfection.