Classical Complement Pathway Inhibition in a "Human-On-A-Chip" Model of Autoimmune Demyelinating Neuropathies.

Area of Science:

• Neuroscience
• Immunology
• Biotechnology

Background:

• Chronic autoimmune demyelinating neuropathies, including CIDP and MMN, are rare disorders with unclear causes.
• Autoantibodies targeting neural components are implicated in their pathogenesis.
• Current models often fail to fully recapitulate disease complexity.

Purpose of the Study:

• To develop and validate a human-on-a-chip (HoaC) model for studying CIDP and MMN.
• To investigate the role of complement pathway activation in these neuropathies.
• To evaluate the therapeutic potential of TNT005, a complement inhibitor.

Main Methods:

• Developed a HoaC model using microelectrode arrays with patient-derived cells.
• Utilized patient sera containing anti-GM1 antibodies to induce neuropathic effects.
• Assessed complement deposition (C3b, C5b-9) and neurophysiological function (action potential frequency, conduction velocity).
• Treated the HoaC model with TNT005 or an isotype control antibody.

Main Results:

• Patient sera induced complement activation and deposition on neural cells in the HoaC model.
• The model demonstrated reduced motoneuron function mirroring CIDP and MMN pathology.
• TNT005 treatment successfully inhibited complement deposition and restored neural function.
• Isotype control antibody showed no significant therapeutic effect.

Conclusions:

• Complement activation by patient autoantibodies is sufficient to cause neurophysiological deficits in autoimmune neuropathies.
• The HoaC model effectively mimics key aspects of CIDP and MMN.
• Complement inhibition with TNT005 shows significant therapeutic promise for these conditions.
• The HoaC model demonstrates translational potential for drug development.