Abstract

The Recent State of Oligonucleotide Therapeutics for Neurological Disorders

Hideki Mochizuki, Professor and Chairman, Osaka University Graduate School of Medicine

Oligonucleotide therapeutics have a wide range of potential applications in the clinic owing to their highly different modes of action such as antisense, ligands and protein inhibitors. In the field of neurology, ASOs that modulate splicing of SMN2 and Dystrophin pre-mRNA were approved for spinal muscular atrophy and Duchenne muscular dystrophy, respectively. siRNA encapsulated in lipid nanoparticle that degrades TTR mRNA was also available for hereditary ATTR amyloidosis. Many others are being developed worldwide, targeting neurological disorders caused by gene mutations and neurodegenerative diseases such as Huntington’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), multiple system atrophy (MSA) and Alzheimer’s disease. Beyond pre-clinical trials, several clinical trials of oligonucleotide therapeutics are ongoing for neurological diseases, whereas phase III trials of tominersen (for Huntington’s disease) and tofersen (for ALS) closed due to failing to attain their primary efficacy endpoints in 2021. We have been developing ASO suppressing SNCA expression as a potential therapy for MSA and PD. In this symposium, we will review the recent state of oligonucleotide therapeutics for neurological diseases including basic science, approved drugs and clinical trials.