Neurovascular Modulation of the Blood-brain Barrier Using Focused Ultrasound for Antisense Therapy Delivery in Amyotrophic Lateral Sclerosis.

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, and the blood-brain barrier (BBB) restricts CNS delivery of macromolecular therapeutics such as antisense oligonucleotides (ASOs). Focused ultrasound (FUS) with microbubbles enables transient, noninvasive opening of the BBB for deliver SOD1-targeted ASOs.

METHODS

A narrative review of the literature in PubMed, Scopus, Web of Science, and Google Scholar (2020-2025) was conducted to evaluate FUS-assisted delivery of SOD1-targeted ASOs, with an emphasis on lipid- and calcium phosphate (CaP)- based nanoparticles.

RESULTS

Preclinical studies showed that FUS-mediated BBB opening (250 kHz; mechanical index 0.33; 30-s exposure; 0.15 mL/kg microbubbles) increased brain accumulation of nanoparticle- encapsulated ASOs by >3.5-fold compared with FUS without microbubbles. CaP lipid nanoparticles (~73 nm; -21 mV; 23-30% encapsulation efficiency) encapsulating tofersen demonstrated pH-responsive intracellular release. In wild-type and G93A SOD1 transgenic mice, FUS combined with CaP-ASO nanoparticles reduced SOD1 expression in sonicated cortical regions and increased lumbar spinal motor-neuron counts without detectable neuroinflammation or tissue damage.

DISCUSSION: Combining FUS-mediated BBB modulation with CaP nanoparticles provides a minimally invasive strategy for CNS ASO delivery. Observed spinal cord effects suggest wider CNS distribution, potentially involving CSF transport and retrograde axonal pathways. Clinical translation requires optimising FUS parameters, conducting long-term safety assessments, and managing skull acoustic variability.

CONCLUSION

MRI-guided FUS combined with CaP lipid nanoparticles represents a promising non-invasive platform for SOD1-targeted ASO delivery and precision gene therapy in ALS.