Antisense Oligonucleotides in Parkinson's Disease: Challenges, Opportunities, and the Promise of Low-Intensity Focused Ultrasound for Brain Delivery.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuronal loss in the basal ganglia, for which no disease modifying therapy is currently available. Antisense oligonucleotides (ASOs) have emerged as promising therapeutic candidates, and numbers of preclinical studies with PD models have demonstrated their potential to inhibit α-synuclein aggregation. However, a major obstacle to clinical application of ASOs in neurodegenerative diseases is their limited permeability across the blood-brain barrier. Consequently, currently approved ASOs for neurological disorders are administered intrathecally, which makes it difficult to achieve efficient drug delivery to deep brain structures such as the basal ganglia. Focused ultrasound (FUS)-induced blood-brain barrier opening has attracted interest as a noninvasive strategy to enhance central nervous system drug delivery. Clinical studies have demonstrated that FUS-mediated blood-brain barrier opening can be performed safely in patients with PD and effective delivery of therapeutic agents, such as glucocerebrosidase. Yet, evidence for effective delivery of ASOs to the brain via FUS-induced blood-brain barrier opening is still lacking. This review summarizes current studies of ASOs in PD, together with recent advances in FUS-mediated blood-brain barrier opening. We highlight remaining biological and translational limitations and outline future perspectives for optimizing ASOs delivery with FUS-mediated blood-brain barrier opening to accelerate disease-modifying therapy for PD.