Classical Complement Pathway Inhibition in a “Human‐On‐A‐Chip” Model of Autoimmune Demyelinating Neuropathies
Open accessAbstract
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.
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A CIDP organ-on-chip model using iPS-derived motor neurons and Schwann cells on microelectrode arrays reproduces clinical features like muscle contraction and electrical activity.
“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.”
From Human disease models in drug development (2023) · cites this paper as [116]
The Introduction (page unavailable) describes a CIDP human-on-a-chip model with iPSC-derived motor neurons and human Schwann cells cultured on microelectrode arrays. The Results (page unavailable) report measurements of electrical activity and conduction velocity, but the paper does not report that the model reproduces muscle contraction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the CIDP organ-on-chip model, TNT005 suppressed immune reaction and restored function, leading the FDA to approve trials.
“Treatment with the antibody TNT005, a specific complement component 1s inhibitor, inhibited the immune reaction and rescued the functional deficits, prompting the FDA to approve clinical trials (NCT04658472).”
From Human disease models in drug development (2023) · cites this paper as [116]
The Results (page unavailable) report that TNT005 inhibited patient-serum-mediated complement deposition and rescued motoneuron functional deficits in the CIDP and MMN chip models. The Abstract says the efficacy data were included in an investigational new drug application, and the Introduction links the model to clinical testing (NCT04658472). Neither passage says the FDA approved trials because of these findings. (LLM, conf=0.87)
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- Authors
- Rumsey, J. W., Lorance, C., Jackson, M., Sasserath, T., McAleer, C. W., Long, C. J., Goswami, A., Russo, M. A., Raja, S. M., Gable, K. L., Emmett, D., Hobson‐Webb, L. D., Chopra, M., Howard, J. F., Guptill, J. T., Storek, M. J., Alonso‐Alonso, M., Atassi, N., Panicker, S., Parry, G., Hammond, T., & Hickman, J. J.
- Affiliations
- Hesperos (United States) (US)
- University of Central Florida (US)
- Duke University (US)
- University of North Carolina at Chapel Hill (US)
- Sanofi (United States) (US)
- Corresponding author
- Hickman, James J.
- ORCID
- Venue
- Advanced Therapeutics
- Publisher
- Wiley
- Published
- 2022-04-19
- Volume
- 5
- Issue
- 6
- ISSN
- 2366-3987 (ISSN-L)
- PMC
- PMC9540753
- OpenAlex
- W4223976622
- Cited by
- 74
- References
- 55
- Citations by year
- 2026: 10 · 2025: 30 · 2024: 19 · 2023: 11 · 2022: 4
- FWCI
- 8.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Advanced Therapeutics (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by-nc-nd)
- UNC Libraries
- Funders
- Sanofi
- National Institutes of Health (R44TR001326)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- classical complement pathway, complement inhibition, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, human-on-a-chip, microelectrode arrays, electrical conduction, Schwann cells, axon growth, action potential frequency, conduction velocity
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