Modeling ALS pathogenesis using human ipsc-derived neuromuscular organoids

The National Institute of Neurological Disorders and Stroke awarded Louisiana State University Health Sciences Center-Shreveport $146,000 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to develop and validate a human neuromuscular organoid platform for modeling amyotrophic lateral sclerosis (ALS) pathology.

The funded research establishes three-dimensional organoid models derived from human induced pluripotent stem cells that integrate spinal motor neurons, skeletal muscle fibers, and glial cells to recapitulate neuromuscular connectivity and junction structure. The project investigates neuromuscular developmental and architectural alterations in ALS organoids compared to isogenic controls, using organoids generated from patient-derived hiPSCs representing juvenile and early-onset ALS subtypes (ALS4 and ALS6). Assessment includes cellular composition, spatial organization, and neuromuscular junction ultrastructure via immunostaining, confocal imaging, and electron microscopy. The work defines functional deficits and synaptic changes in ALS organoids using multielectrode array recordings and pharmacological modulation of synaptic activity.

The period of performance runs from September 1, 2026, through August 31, 2028, with performance at LSU Health Sciences Center-Shreveport in Shreveport, Louisiana. The assistance type is a project grant.

Abstract

Title: modeling ALS pathogenesis using human ipsc-derived neuromuscular organoids three-dimensional (3D) organoid models derived from human induced pluripotent stem cells (ipscs) have emerged as powerful tools for studying human development and disease in vitro. Neuromuscular organoids (nmos), which integrate spinal motor neurons, skeletal muscle fibers, and glial cells, are particularly promising for modeling motor circuitry and neuromuscular junctions (nmjs), the synapses essential for voluntary muscle control. Despite recent advances, current NMO models often lack structural and functional maturity, and their ability to accurately replicate human neuromuscular connectivity and physiology remains limited. Furthermore, their potential as disease models, especially for motor neuron disorders such as amyotrophic lateral sclerosis (ALS), has yet to be fully realized. This proposal seeks to establish and validate a physiologically relevant NMO platform and apply IT to model ALS pathology. We hypothesize that self-organizing nmos derived from human ipscs can recapitulate the cellular, structural, and functional features of the human neuromuscular system and yield mechanistic insight into ALS. In aim 1, we will investigate neuromuscular developmental and architectural alterations in ALS nmos compared to isogenic controls. Nmos will be generated from hipscs derived from juvenile and early-onset ALS subtypes (ALS4 and ALS6) and assessed for cellular composition, spatial organization, and NMJ ultrastructure using immunostaining, confocal imaging, and electron microscopy. In aim 2, we will define functional deficits and synaptic changes in ALS nmos using multielectrode array (MEA) recordings and pharmacological modulation of synaptic activity. Successful completion of this project will yield a reproducible, functional human NMO platform for studying neuromuscular development, disease mechanisms, and therapeutic responses. This work will advance organoid technology and address a critical GAP in ALS modeling by providing a scalable, human-relevant system for mechanistic investigation and future drug screening.