Blood-brain barrier disruption for the delivery of non-infectious viral vectors and proteins, preliminary study

Angelman syndrome (AS) is a rare neuro-genetic disorder caused by loss of expression of the maternal copy of UBE3A in the brain inducing severe mental and physical impairments. Due to brain-specific genetic imprinting, the paternal UBE3A is silenced by a long antisense transcript. Inhibition of the antisense transcript could lead to unsilencing of paternal UBE3A, thus providing a therapeutic approach for AS. Treatment requires widespread delivery of gene regulators to the brain. Safe blood-brain barrier (BBB) disruption using focused ultrasound (FUS) combined with microbubbles has shown promising results in cancer applications and several clinical studies are underway. In this study, our goal is to deliver therapeutic agents to treat AS using FUS. Deverman et al. demonstrated that peptide PHP.B, when displayed on the 20-nm AAV9 capsid surface (AAV-PHP.B), enhanced neuronal transfection throughout the brain by 40-fold following IV injection in healthy mouse models [1]. Here, we seek to determine whether delivery of a construct with wide brain distribution can be augmented by enhancing the BBB transport. In this work, a 128-element 1.5 MHz therapeutic array was interfaced to the Vantage platform (Verasonics). In a mouse model, the BBB was successfully disrupted over an expanded treatment area by rapidly translating the beam along a predetermined pattern (swept focus) or by generating multiple foci simultaneously (multifoci). Comparing BBB disruptions with 16 foci and with a swept focus, no significant differences were found, suggesting that a multifoci approach can increase the disrupted area while reducing the number of transmission. Preliminary data obtained through immunofluorescence microscopy showed increased intensity in the MB-FUS+AAV-PHP.B group compared to the AAV-PHP.B group.