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Updated: Aug 28, 2026

Lumbar Intrathecal Injection of SOD1-ASOs for Precise CNS Targeting and Predictive Efficacy in Human SOD1-G93A ALS Mice
Published on: February 24, 2026
Combination Pharmacology for ALS: A Mechanistic Rationale
Jeffrey Rosenfeld1, Shiran Salomon-Zimri2, Ferenc Tracik2
1Center for Restorative Neurology, Department of Neurology, Loma Linda University Health, Loma Linda, CA 92354, USA.
Abstract:
Amyotrophic lateral sclerosis (ALS) involves multiple converging pathogenic mechanisms, including glutamate excitotoxicity, oxidative and endoplasmic-reticulum stress, mitochondrial dysfunction, neuroinflammation, iron dysregulation, and altered microRNA processing. Expecting a single pharmacologic intervention to meaningfully alter such a complex disease has proven overly optimistic and is reflected by the modest clinical benefits of approved monotherapies. This review outlines the mechanistic foundation and translational rationale for combination pharmacology in ALS. Drawing from paradigms in oncology, infectious disease, and other neurological disorders, it explores how rational multi-target strategies, whether synergistic, complementary, or pathway-divergent, may better address the multifactorial biology of ALS. The review also discusses recent mechanistic examples and design principles for advancing this therapeutic paradigm.
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