Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10-15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.

Over the past two decades, elucidation of the genetic defects that underlie cancer has resulted in a plethora of novel targeted cancer drugs. Although these agents can initially be highly effective, resistance to single-agent therapies remains a major challenge. Combining drugs can help avoid resistance, but the number of possible drug combinations vastly exceeds what can be tested clinically, both financially and in terms of patient availability. Rational drug combinations based on a deep understanding of the underlying molecular mechanisms associated with therapy resistance are potentially powerful in the treatment of cancer. Here, we discuss the mechanisms of resistance to targeted therapies and how effective drug combinations can be identified to combat resistance. The challenges in clinically developing these combinations and future perspectives are considered.