Antisense oligonucleotides (ASOs) in motor neuron diseases: a road to cure in light and shade

• DOI: 10.20944/preprints202402.1738.v1
• Publication Date: 2024-03-06T02:50:00Z
• Authors: Silvia Cantara; Giorgia Simoncelli; Claudia Ricci
• Keywords: 0303 health sciences; spinal and bulbar muscular atrophy; Amyotrophic Lateral Sclerosis; nusinersen; 610; amyotrophic lateral sclerosis; antisense oligonucleotides (ASOs); clinical trials; innovative therapy; motor neuron diseases; nusinersen; spinal and bulbar muscular atrophy; spinal muscular atrophy; tofersen; clinical trial; Review; Oligonucleotides, Antisense; tofersen; Muscular Atrophy, Spinal; 03 medical and health sciences; antisense oligonucleotides (ASOs); 616; motor neuron disease; Humans; Animals; amyotrophic lateral sclerosi; Motor Neuron Disease; innovative therapy; spinal muscular atrophy

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins and decrease levels of toxic proteins. ASOs are being developed for the treatment of several diseases, including motor neuron diseases (MNDs), a group of neurodegenerative disorders characterised by the loss of motor neurons, including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MND, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.