# From Dish to Trial: Building Translational Models of ALS

## TL;DR

This paper reviews how patient-derived stem cells and 3D models are improving our understanding of ALS and aiding drug development.

## Contribution

The paper highlights novel iPSC-based models and frameworks for ALS drug development and clinical trial design.

## Key findings

- Patient-derived iPSCs enable human-relevant modeling of ALS pathology.
- 3D cultures and ALS-on-a-chip systems enhance mechanistic understanding of ALS.
- Large iPSC cohorts and patient stratification may improve clinical trial success.

## Abstract

What are the main findings?
Patient-derived iPSCs enable human-relevant modeling of ALS pathology.3D cultures and ALS-on-a-chip systems improve mechanistic understanding of ALS.

Patient-derived iPSCs enable human-relevant modeling of ALS pathology.

3D cultures and ALS-on-a-chip systems improve mechanistic understanding of ALS.

What are the implications of the main findings?
Large-scale sporadic cohorts may support ALS clinical trials.Proposed iPSC framework for ALS drug development.

Large-scale sporadic cohorts may support ALS clinical trials.

Proposed iPSC framework for ALS drug development.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced pluripotent stem cells (iPSCs) have reshaped our understanding of ALS pathogenesis and emerged as a promising translational platform for therapy development. ALS modeling has further expanded with the advent of three-dimensional systems, including ALS-on-chip platforms and organoid models, which better capture cell–cell interactions and tissue-level phenotypes. Despite these advances, effective disease-modifying therapies remain elusive. Recent clinical trial setbacks highlight the need for improved trial design alongside robust, translational iPSC models that can better predict therapeutic response. Nonetheless, the outlook is promising as large iPSC patient cohorts, quantitative phenotyping combined with genetically informed patient stratification, and reverse translational research are beginning to close the gap between in vitro discovery and clinical testing. In this review, we summarize the major advances in iPSC technology and highlight key iPSC-based studies of sporadic ALS. We further discuss emerging examples of iPSC-informed therapeutic strategies and outline the challenges associated with translating iPSC-derived mechanistic insights and pharmacological findings into successful clinical therapies.