The body slowly loses its ability to move, one neuron at a time. Simple actions such as walking, speaking and eventually even breathing are gradually taken away. These outcomes are part of amyotrophic lateral sclerosis (ALS): a rare and devastating disease that progressively strips away a person’s voluntary movements while leaving cognition largely intact.
Over three decades after riluzole’s approval, the protein-blocking drug remains the gold standard of ALS treatment. Yet, patients with ALS on riluzole still gain only a few extra months of life on average. More recently, new gene therapies such as tofersen, an antisense oligonucleotide drug targeting SOD1 gene mutations, have shown that new antisense oligonucleotide-based treatments can slow ALS’s progression; but only in a small subset of patients with rare genetic forms thereof.
“Tofersen’s discovery inspired our team to explore broader antisense oligonucleotide strategies for ALS,” said Dave Keng Boon Wee and Shi-Yan Ng, Principal Investigators at the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB) and A*STAR Genome Institute of Singapore (A*STAR GIS) respectively. “About 95 percent of patients have forms of ALS with unknown disease-causing mutations but identical symptoms, which convinced us that there must be shared disease mechanisms.”
In a recent investigation, a team comprising Wee, Ng and A*STAR IMCB colleagues worked with the National University of Singapore, and the University of Queensland, Australia, to focus on BLOC1S1, a gene they had previously found to be elevated in ALS motor neurons.
“In 2020, we found that motor neurons that degenerate in ALS have defective mitochondria that can’t produce enough energy to meet the cells’ high energy demands,” said Ng. “High levels of BLOC1S1 promote these defects.”
To test the functional effects of reducing BLOC1S1 levels, the team developed splice-switching oligonucleotides (SSOs): short RNA-targeting molecules designed to alter RNA processing and thereby reduce BLOC1S1 expression. While SSOs are a subclass of antisense oligonucleotides, they differ from tofersen, modulating gene expression rather than targeting specific mutations.
“SSOs are like molecular roadblocks,” Wee explained. “In this case, we placed a roadblock on the BLOC1S1 track, effectively reducing its output.”
The team found that across multiple disease models of ALS, lowering BLOC1S1 with SSOs helped restore mitochondrial performance, while high levels exacerbated their dysfunction and disrupted cellular energy generation. In human stem cell-derived motor neuron models, that improved mitochondrial function paired with extended cell survival; in ALS mouse models, disease progression was delayed, while both lifespan and disease-free survival increased.
“Improved motor neuron survival is especially important because ALS is defined by their progressive loss,” Ng noted, adding that BLOC1S1 targeting appears to work well multiple ALS genetic subtypes.
The team’s SSO technology has been patented as a therapeutic candidate for ALS treatment. Future work may evaluate its efficacy in mouse models of TDP-43 proteinopathy, a pathological hallmark present in up to 97 percent of ALS cases.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB) and A*STAR Genome Institute of Singapore (A*STAR GIS).
