Enhancing the delivery of SOD1 antisense oligonucleotides to the murine brain using lipid nanoparticles and image-guided focused ultrasound

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. Abnormal accumulation of misfolded and aggregated proteins in the soma of motor neurons is one of the main pathological hallmarks of ALS. Hence, reducing the burden of misfolded protein in motor neurons has emerged as a promising therapeutic approach to control the disease. Antisense oligonucleotides (ASOs) carry the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, the extremely poor blood-brain barrier (BBB) penetration of ASOs and invasiveness of current intrathecal delivery methods, warrant the development of alternative strategies for the delivery of ASOs to the central nervous system (CNS). In the current study, we report the effective delivery of a next-generation SOD1 ASO (Tofersen) into the brain of mice using calcium phosphate lipid nanoparticles following systemic delivery. Most importantly, for the first time, we demonstrate the superior capability of transcranial focused ultrasound (FUS) with intravenously administered microbubbles to significantly improve the delivery of ASO-loaded nanoparticles into the mouse brain compared to control mice receiving FUS without microbubbles. Histological examination in combination with contrast enhanced MRI suggests that the opening of the BBB in this context is transient and without evidence of any perturbation in the neural micro environment, parenchymal injury or necrosis indicating the treatment is well tolerated. Further in vivo evaluation of this strategy could lead to the development of a promising new approach for therapeutic delivery to treat ALS in patients.