How Ionis' antisense drugs could help combat ALS and dementia

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two fatal neurodegenerative diseases marked by different clinical signs. But they are believed to be caused by a common underlying mechanism: a mutation in the C9orf72 gene that leads to the toxic accumulation of the TDP-43 protein.

Now, scientists at Mayo Clinic and the University of Pennsylvania are providing additional insight into the problem by shedding light on the role of another protein called poly(GR) in TDP-43 aggregation.

The researchers discovered that drugs called antisense oligonucleotides developed by Ionis Pharmaceuticals reduced TDP-43 as well as neurodegeneration in mice with mutated C9orf72, they reported in a new study published in Science Translational Medicine. 

Many ALS and FTD cases are linked to the abnormal expansion of nucleotide G4C2 repeats in C9orf72, which results in the transcription of different proteins, including poly(GR). Antisense oligonucleotides—single-stranded RNAs that are designed to inhibit the translation of target mRNA into harmful proteins—are considered to be a promising approach to combating the problem. Biogen’s Ionis-partnered antisense drug BIIB078 is in a phase 1 trial in adults with C9orf72-associated ALS, with data expected next year.

RELATED: Fighting ALS, dementia and more by trapping toxic brain proteins

The Mayo Clinic and Penn researchers studied the behavior of pure TDP-43 and found that poly(GR) accelerated and enhanced TDP-43 aggregation in lab dishes and in the brains of mice. Poly(GR) contributed to the buildup mainly by disrupting how proteins were transported between the cytoplasm and nucleus in neurons, the team found.

After demonstrating that poly(GR) is directly responsible for inducing the TDP-43 problem, the scientists went on to test whether antisense oligonucleotides targeting G4C2 repeats (c9ASOs) could alleviate TDP-43 aggregates. 

They injected c9ASOs into the brain of G4C2-mutated mice. The treatments significantly reduced levels of poly(GR) and TDP-43. What’s more, the researchers found that the drugs prevented the loss of neurons otherwise observed in the G4C2 mice and protected neurons from injury, as indicated by a biomarker called plasma neurofilament light.

TDP-43 has been the focus of many studies aimed at combating ALS and FTD. Researchers at the University of Pittsburgh developed what they called “bait-oligonucleotides” that mimic RNA binding partners, which, when deficient, appear to help form toxic TDP-43 clumps. Another team at Harvard University suggested that repairing the STMN2 gene—which they found changed in lockstep with TDP-43—could be a potential new way for treating ALS.

The study from the Mayo Clinic and Penn further clarified the mechanism by which poly(GR) drives TDP-43 pathology, confirming that G4C2-targeted oligonucleotides hold promise against neurodegenerative diseases, the researchers said in the study.