Evaluation of Pegcetacoplan in Ameliorating ALS Disease Phenotypes Using a Human-on-a-Chip Neuromuscular Junction System


Translational Research

Poster Number: 153


Scott Baver, PhD, Apellis Pharmaceuticals, Virginia Smith, Hesperos, Inc., Ashley Robertson, Leticia Lenkiu, Helena Cooper, Heather Cannon, Daisy Martinez, Hannah Hanson, James Hickman

The complement system is a crucial component of innate immunity and is associated with pathogenesis of numerous diseases, including amyotrophic lateral sclerosis (ALS). Upregulation of complement proteins in ALS rodent models has been linked to neuroinflammation, although the contribution of disease progression is still unclear. Additionally, complement (eg, C3 and C5) activation products are elevated in people with ALS and may trigger an inflammatory response leading to motoneuron death. Inhibition of complement C3 activation with pegcetacoplan could preserve the neuromuscular junction (NMJ) and unlock a possible therapeutic pathway for ALS. However, preclinical models to evaluate the effect of the complement system and potential therapeutic interventions on NMJ function are necessary.
This study aims to describe the potential applications of a human-on-a-chip model system designed to evaluate the role of C3 inhibition on NMJ formation, fidelity, physiology, and complement deposition in humans in vitro with pegcetacoplan.
The human-on-a-chip neuromuscular system is an in vitro platform with superoxide dismutase (SOD1) (E100G) or TAR DNA binding protein (TDP-43) motoneurons derived from iPSCs and wild-type (WT) microglia separated by microtunnels from iPSC-derived SOD1 (E100G) skeletal muscle, Schwann cells, and THP-1 monocytes/macrophages. These systems are cultured with or without complement sera and received pegcetacoplan or control. The motoneuron side of the chamber received electrical stimulation, and skeletal muscle contraction is monitored in real time.
Complement C3 and C5 deposition may help assess the impact of complement sera and pegcetacoplan on NMJ function (assessed by NMJ number and fidelity) in ALS-like disease and WT model systems. Synchronous contractions of ALS-like disease and WT model systems at various stimulation frequencies can also be investigated using this model.
This study using a human-on-a-chip model is anticipated to generate the earliest evidence that modulating C3 has a role in ALS disease progression.