Classical Complement Pathway Inhibition in a “Human‐On‐A‐Chip” Model of Autoimmune Demyelinating Neuropathies

Abstract

Chronic autoimmune demyelinating neuropathies are a group of rare neuromuscular disorders with complex, poorly characterized etiology. Here the authors describe a phenotypic, human-on-a-chip (HoaC) electrical conduction model of two rare autoimmune demyelinating neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), and explore the efficacy of TNT005, a monoclonal antibody inhibitor of the classical complement pathway. Patient sera is shown to contain anti-GM1 IgM and IgG antibodies capable of binding to human primary Schwann cells and induced pluripotent stem cell-derived motoneurons (MNs). Patient autoantibody binding is sufficient to activate the classical complement pathway, resulting in detection of C3b and C5b-9. A HoaC model, using a microelectrode array with directed axonal outgrowth over the electrodes treated with patient sera, exhibits reductions in MN action potential frequency and conduction velocity. TNT005 rescued the serum-induced complement deposition and functional deficits while treatment with an isotype control antibody has no rescue effect. These data indicate that complement activation by CIDP and MMN patient serum is sufficient to mimic neurophysiological features of each disease and that complement inhibition with TNT005 is sufficient to rescue these pathological effects and provide efficacy data included in an investigational new drug application, demonstrating the model's translational potential.

Human disease models in drug development

“…Another successful example is the use of OoC models of chronic inflammatory demyelinating polyneuropathy, an autoimmune disease that cause muscle weakness, conduction blocks and aberrant spinal reflexes 116 . An OoC-based chronic inflammatory demyelinating polyneuropathy electrical conduction model, consisting of human iPS cell-derived motor neurons and Schwann cells cultivated on microelectrode arrays, closely emulates clinically relevant features such as muscle contraction and electrical activity.…”

Poor Translatability of Biomedical Research Using Animals — A Narrative Review

“…243,244 Recently, the US Food and Drug Administration (FDA) accepted efficacy data from an organ-on-a-chip as part of an Investigational New Drug (IND) submission for clinical trial. 245 We recommend that readers access Ingber’s recent article on organs-on-chips, 246 for a more comprehensive review than is possible in this current paper, where we provide just one example to explore the promise of this technology.…”

A functional neuron maturation device provides convenient application on microelectrode array for neural network measurement

“…Changes in axon conduction velocity are commonly used for clinical diagnosis of peripheral neuropathy. Previous in vitro studies direct axonal alignment in polydimethylsiloxane models and show conduction velocity changes under drug administration [ 54 , 55 ]. The SCAD device also allowed the unidirectional alignment of axons and, consequently, enabled to reproduce the axon conduction velocity of DRG neurons in culture on SCAD devices as measured using the CMOS–MEA system.…”