Pathway Interconnections in ALS Necessitate a Shift to Combination Therapies

Abstract

Summary for Layman: ALS and the Potential of Combination Therapies Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease where nerve cells responsible for controlling movement, known as motor neurons, gradually deteriorate and die. As these motor neurons degenerate, people with ALS experience increasing muscle weakness, loss of mobility, and eventually, difficulty breathing. The disease progresses rapidly, making ALS particularly devastating. Approximately 10% of ALS cases are inherited, caused by genetic mutations passed down through families. The remaining 90% are sporadic, meaning they occur without a known family history or specific genetic cause. In these sporadic cases, ALS likely results from a complex interplay of genetic predispositions, environmental exposures, and lifestyle factors that together trigger the disease unexpectedly. Since no single test can confirm ALS, diagnosis is challenging, often causing delays that allow significant motor neuron damage to occur before the disease is recognised. Treating ALS is especially difficult, because nerve cell damage is usually irreversible and driven by several interconnected processes. Oxidative stress, a condition where highly reactive oxygen molecules damages cellular components and triggers the aggregation of abnormal proteins within cells. These protein aggregates contribute to mitochondrial dysfunction and inflammation. As mitochondria lose function, they produce release harmful molecules, further worsening oxidative stress and activating the immune response. This cascade intensifies excitotoxicity, where neurons become overstimulated by chemical signals, ultimately contributing to cell death. Most current treatments focus on a single pathway, aiming for instance, to reduce protein clumping or limit excitotoxicity. However, these single-target approaches have not been able to halt or reverse ALS progression. Therefore, a combination of therapies that target multiple pathways simultaneously must be explored. By addressing several sources of cellular dysfunction together, these therapies have the potential to slow down or even interrupt the damaging cycle of that drives motor neuron loss. Many promising therapeutic candidates for ALS have shown potential in preclinical studies, only to fail in clinical trials. While some of these treatments may have influenced specific pathways, the relentless progression of motor neuron degeneration could still have been drive by other processes. For many candidate therapies we may never know if these interventions had any biological impact, as clinical trials rely on validated outcome measures which in ALS research are typically broad measures like survival time or the ALS Functional Rating Scale-Revised, which reflects overall function, but does not capture changes in underlying cellular mechanisms. To improve the precision of ALS research and treatment, biomarkers—biological indicators that reflect activity at the cellular level—are crucial. Biomarkers could enable researchers to track the effects of treatments of specific pathological pathways, helping to determine if a therapy is influencing underlying disease mechanisms, even if it doesn’t immediately improve overall function. By including a panel of biomarkers in clinical trials, researchers can gain valuable insights into whether treatments effectively target protein aggregation, oxidative stress, mitochondrial dysfunction, excitotoxicity, or neuroinflammation. This approach not only improves our understanding of how potential therapies interact with ALS pathology but also guides the development of future combination therapies tailored to address multiple processes simultaneously.