Advancing the Translational Pipeline: From In Vivo and In Vitro 2D Models to Next-Generation Cell Culture Models for Amyotrophic Lateral Sclerosis Modelling and Drug Discovery
Abstract
Background: Amyotrophic lateral sclerosis (ALS) is still a global health challenge, as there is no effective treatment due to the inadequacy of conventional experimental platforms for comprehending pathogenic mechanisms and developing therapy. Objectives: This review details the recent progress and clinical utility of next-generation iPSC-derived 3D in vitro systems integrated with microfluidics, CRISPR-Cas9 gene editing, multi-omics readouts, and AI-based machine learning, which are emerging as transformative platforms for recapitulating key ALS pathological hallmarks. Methods: A literature search was performed using PubMed and Web of Science, including only English-language publications. All the published papers collected covered the period from January 2015 to June 2026. Results: Human induced pluripotent stem cell (iPSC) cerebral organoids, assembloids, and organ-on-a-chip technologies are revolutionizing research into ALS by providing a way to model the complex spatial organization, cellular heterogeneity, and neural network dynamics of the human brain. Moreover, recent bioengineering advancements enable the inclusion of functional neurovascular units, the integration of resident immune cells (microglia), and the use of 3D bioprinting to accelerate the functional maturation of age-related phenotypes. CRISPR-Cas9 genome editing, OMICS, and machine learning improve tools for studying ALS and identifying therapeutic targets. Conclusions: Novel cell culture models may bridge the gap between preclinical animal models and human clinical trials and reduce the duration and costs of translation. Future work is likely to integrate bioprinting with organ-on-chip microfluidics, CRISPR-based genetic editing, and multi-omics readouts to build increasingly faithful, patient-specific ALS models for both basic research and precision therapeutics.
