A recent publication provides a detailed overview of recent advances and challenges in the development of RNA therapies for neurodegenerative diseases, particularly for amyotrophic lateral sclerosis (ALS).
Early immunotherapies targeting amyloid-β in Alzheimer's disease initially showed reductions in amyloid plaques but failed to prevent cognitive decline. The FDA recently approved lecanemab as the first disease-modifying drug for Alzheimer's disease. However, its benefits appear to be limited to the early stages of the disease, as it does not stop neurodegeneration or improve cognition. This highlights the difficulty of modifying neurodegenerative diseases, which often progress despite treatment.
Most cases of ALS are recognized as proteinopathies involving RNA dysregulation, but in others, such as those with mutations in superoxide dismutase 1 (SOD1), these abnormalities are absent, suggesting different pathogenetic pathways.
Nucleic acid-based therapies (NATs) represent an emerging treatment class that targets RNA rather than proteins. These agents act by degrading disease-associated mRNA or altering translation processes. For example, ASOs inhibit translation by disrupting ribosome assembly or degrading mRNA.
Although ASO approaches are both reasonable and scientifically sound, discernible clinical benefit has not always been observed in humans.
Three clinical trials using ASOs to reduce huntingtin (HTT) protein in Huntington’s disease have been halted because the therapies did not consistently reduce mutant HTT levels or improve clinical outcomes. A trial of one ASO, tominersen, caused unexpected worsening in patients who received higher doses. This has raised concerns about potential ASO toxicity due to off-target effects, immune responses, or loss of normal HTT function, which is essential for cellular health.
ASOs targeting toxic genes in ALS, such as TDP-43 in ALS, have shown promise in preclinical studies in extending life and restoring motor function in animal models. Yet, inhibitions of SOD1 and C9orf72 in mice show motor deficits and memory impairment over time, warning researchers of the potential risks of long-term ASO treatments. Clinical trials, such as the Phase III study of tofersen (an ASO targeting SOD1), have demonstrated a reduction in SOD1 mRNA, although clinical (i.e. visible) benefit has not been established.
Results from a Phase III trial of the ASO tofersen, which targets SOD1 mRNA in ALS, were reported in 2022. In this study, a total of 108 participants were enrolled, 60 of whom were classified in the faster progression subgroup. Approximately 7% of participants receiving tofersen experienced serious neurological adverse events, including myelitis, chemical or aseptic meningitis, and lumbar radiculopathy, but the pharmaceutical and medical community has highlighted the case of a Swedish patient who saw real benefit from his therapy.
A new study, ATLAS (NCT04856982), aims to test tofersen in asymptomatic, and some are thought to be presymptomatic, carriers of the SOD1 mutation to determine whether early intervention can delay the onset of ALS.
ASO-mediated inactivation in neurodegenerative diseases faces major challenges. By the time symptoms of ALS appear, motor neuron damage may be too advanced. Symptoms appear because compensatory mechanisms are exhausted. This is similar to Parkinson’s disease, where symptoms only appear after significant neuronal loss.
It is also likely that current ASOs are not very selective, and may reduce the production of essential proteins, causing side effects. Targeting mutations or aberrant transcripts specifically with more selective ASOs, such as those used in the PRECISION-HD trials, could help preserve healthy protein function.
Identifying sensitive biomarkers, such as elevated plasma TDP-43 or cryptic HDGFL2 levels, could help diagnose ALS before symptoms appear. This could allow for timely therapeutic interventions to slow or prevent neurodegeneration before it becomes irreversible.
In summary, RNA-based therapies such as ASOs offer hope for neurodegenerative diseases but face significant challenges.