Non-invasive delivery of small interfering rubonucleic acid for reduction of Huntingtin expression in the brain is achieved using focused ultrasound to disrupt the blood-brain barrier

Huntington's disease (HD) is caused by a mutation in the Huntingtin (Htt) gene which leads to neuronal dysfunction and cell death. Silencing of the Htt gene can halt or reverse the progression of the disease suggesting that RNA interference is an effective strategy for disease treatment. However, siRNA does not cross the blood-brain barrier (BBB) and therefore delivery to the brain is limited. Here, we demonstrate that focused ultrasound (FUS), combined with intravascular microbubble contrast agent, can locally and transiently disrupt the BBB and deliver siRNA into the brain. We disrupted the BBB in the right striatum of adult rats and delivered siRNA intravenously. 48 hrs following treatment, the right (treated) and left (control) striatum were dissected and analyzed for Htt mRNA levels. We observed a significant reduction in Htt expression in the right, treated striatum, in a dose dependent manner. Furthermore, reduction of Htt was positively correlated with the extent of BBB disruption. This study demo...