A Pilot Study to Develop Paraneoplastic Cerebellar Degeneration Mouse Model

Faure, Fabrice; Yshii, Lidia; Renno, Toufic; Coste, Isabelle; Joubert, Bastien; Desestret, Virginie; Liblau, Roland; Honnorat, Jérôme

doi:10.1007/s12311-023-01524-6

Cited by 1 publication

(1 citation statement)

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“…After establishing that autoantibodies play a pivotal role in sensory neuron sensitization and mechanical hypersensitivity in anti-CV2/CRMP5 autoimmune neuropathy, our next goal was to determine if paraneoplastic neurological syndromes could be replicated preclinically allowing for further mechanistic investigation and determination of potential therapeutic strategies. Interestingly, direct infusion of patient autoantibodies into animals often failed to fully replicate the symptoms seen in paraneoplastic neurological syndromes (27, 28). To overcome this challenge, we adopted an alternative approach: DNA immunization (29).…”

Section: Resultsmentioning

confidence: 99%

Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain

Martin,

Stratton,

Gomez

et al. 2024

Preprint

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Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.

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Section: Resultsmentioning

confidence: 99%