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.

A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

“…FUS +MB is a promising technique facilitating temporary BBB opening (28) with its clinical safety and effectiveness in ALS confirmed by a pioneering study (32). While reversibly increasing the permeabilisation of the BBB to applied drugs in animal studies (29)(30)(31), FUS +MB has not yet been combined with any therapeutic molecule in ALS patients.…”

“…Different ALS drugs were successfully delivered across the BBB with FUS +MB in the animal studies (29)(30)(31). Yet, improving ALS drug delivery with FUS +MB has not been trialled in the human ALS BBB in vitro or ALS patients.…”

“…Focused ultrasound combined with activated microbubbles (FUS +MB ) is an innovative method facilitating temporary BBB opening, therefore enabling targeted CNS drug delivery (28). In animal studies, the application of FUS +MB aided in the delivery of ALS therapeutics across the BBB (29)(30)(31), providing additional therapeutic benefit as compared to the drug alone (30,31). In the first-in-human clinical study, FUS +MB induced a transient increase in the leakage of contrast agent across the BBB in the motor cortex of four patients demonstrating the safety and feasibility of BBB opening in ALS (32).…”