Unique human neuromuscular junction assay establishes skeletal muscle as a key player in ALS



In a recent study published in Biomaterials, a team of researchers led by Hesperos Chief Scientist Dr. J. Hickman established a significant finding to better understand ALS etiology and potential new treatment targets.  Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a debilitating disease that expresses as progressive muscle weakness and loss of motor function typically leading to death within 2-5 years of diagnosis. Researchers continue to work to understand what is driving that dysfunction but progress has been slow primarily due to the limited availability of human-based models. This study used human induced pluripotent stem cells in a microphysiological system (MPS) that compared wild type (healthy) cells against patient derived mutant (diseased) cells. Specifically, the team looked at the relative contributions of diseased skeletal muscle and motoneurons on disease pathophysiology.  

Results from the MPS disease model indicated a significant reduction in the number of functional neuromuscular junctions (NMJ’s), stability of those NMJ’s that did form, and an increased fatigue index which are all clinically relevant readouts.  While the root cause of ALS still remains unresolved, the study produced findings that suggest diseased skeletal muscle plays a significant role in NMJ signal disruption, independent of motoneurons. Ultimately, these results suggest that therapeutically targeting the diseased muscle may be more critical than targeting diseased motoneurons to slow disease progression in addition to further validating the human-on-a-chip platform for further research.

  • “While a treatment is still a ways off, gaining further visibility into the root causes of primary symptoms is a significant step along that path.  Having a functional, clinically relevant human-based NMJ platform is helping us rapidly advance towards treatments for this devastating disease, all without exposing the patient directly.” 

 - James J. Hickman, PhD, Chief Scientist, Hesperos and Professor University of Central Florida

The neuromuscular junction is the point where motoneurons connect with skeletal muscle and is responsible for transmitting signals that dictate movement.  Disruption of that signal is the source of many diseases presenting with impaired motor function, ALS being among the most widespread.  Understanding the mechanisms behind NMJ impairment is key to understanding the root cause because this is one of the earliest events in disease progression.  Now having a clinically relevant, functional NMJ model, researchers have unprecedented visibility into this debilitating disease and is expected to accelerate progress towards an effective treatment. 

More than 200,000 people are living with ALS and approximately 90% of cases are labeled as sporadic, meaning there is no known cause (the remainder of cases rooted in familial genetics).  Today, ALS associated mutations have been identified in over 50 genes including SOD1 and FUS (among others) that have been linked to both sporadic and familial ALS.   The research done in this study is an extension of work done by (mostly) the same team in a 2020 study published in Advanced Therapeutics

Read the full study published in Biomaterials, October 2022: doi.org/10.1016/j.biomaterials.2022.121752

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