2. Academic Validation
  3. Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy

Lipid nanoparticles and transcranial focused ultrasound enhance the delivery of SOD1 antisense oligonucleotides to the murine brain for ALS therapy

  • J Control Release. 2025 Feb 10:378:221-235. doi: 10.1016/j.jconrel.2024.11.074.
Gayathri R Ediriweera 1,  Amal J Sivaram 1,  Gary Cowin 2,  Mikayla L Brown 3,  Luke McAlary 3,  Jeremy S Lum 4,  Nicholas L Fletcher 1,  Liam Robinson 3,  Joshua D Simpson 5,  Liyu Chen 6,  Joanna M Wasielewska 7,  Ella Byrne 3,  John W Finnie 8,  Jim Manavis 8,  Anthony R White 7,  Justin J Yerbury 3,  Kristofer J Thurecht 1,  Kara L Vine 9
Affiliations

Affiliations

  • 1 Centre for Advanced Imaging and Australian Institute for Bioengineering & Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia.
  • 2 Centre for Advanced Imaging and Australian Institute for Bioengineering & Nanotechnology (AIBN), The University of Queensland, Brisbane, QLD 4072, Australia; National Imaging Facility, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 3 School of Chemistry and Molecular Bioscience, Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
  • 4 School of Chemistry and Molecular Bioscience, Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia; School of Medical, Indigenous and Health Sciences, Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia.
  • 5 Louvain Institute of Biomolecular Science and Technology, Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
  • 6 Queensland Brain Institute (QBI), The University of Queensland, Brisbane, QLD 4072, Australia.
  • 7 Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; Faculty of Medicine, The University of Queensland, Brisbane, QLD 4072, Australia.
  • 8 Faculty of Health and Medical Sciences, School of Biomedicine, University of Adelaide, Adelaide, SA 5000, Australia.
  • 9 School of Chemistry and Molecular Bioscience, Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia. Electronic address: [email protected].
PMID: 39645085 DOI: 10.1016/j.jconrel.2024.11.074
Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. One key pathological feature of ALS is the abnormal accumulation of misfolded proteins within motor neurons. Hence, reducing the burden of misfolded protein has emerged as a promising therapeutic approach. Antisense Oligonucleotides (ASOs) have the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, ASO delivery to the central nervous system (CNS) is hindered by poor blood-brain barrier (BBB) penetration and the invasiveness of intrathecal administration. In the current study, we demonstrate effective systemic delivery of a next-generation SOD1 ASO (Tofersen) into the brain of wildtype and G93A-SOD1 transgenic C57BL/6 mice using calcium phosphate lipid nanoparticles (CaP lipid NPs). We show that transcranial focused ultrasound (FUS) with intravenously administered microbubbles can significantly enhance ASO-loaded nanoparticle delivery into the mouse brain. Magnetic resonance imaging (MRI) and immunohistological analysis showed reduced SOD1 expression in the FUS-exposed brain regions and increased motor neuron count in the spinal cord of treated mice suggesting decreased motor neuron degeneration. Importantly, the BBB opening was transient without evidence of structural changes, neuroinflammation or damage to the brain tissue, indicating that the treatment is well tolerated. Overall, our results highlight FUS-assisted nanoparticle delivery of ASOs as a promising non-invasive therapeutic strategy for the treatment of ALS and CNS diseases more broadly.

Keywords

Antisense oligonucleotide; Blood brain barrier; Focused ultrasound; Lipid nanoparticles; Motor neuron disease.

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