Intranasal anti‐caspase‐1 therapy preserves myelin and glucose metabolism in a model of progressive multiple sclerosis
Bibliographic record
Abstract
Inflammatory demyelination and axonal injury in the central nervous system (CNS) are cardinal features of progressive multiple sclerosis (MS), and linked to activated brain macrophage-like cells (BMCs) including resident microglia and trafficking macrophages. Caspase-1 is a pivotal mediator of inflammation and cell death in the CNS. We investigated the effects of caspase-1 activation and its regulation in models of MS. Brains from progressive MS and non-MS patients, as well as cultured human oligodendrocytes were examined by transcriptomic and morphological methods. Next generation transcriptional sequencing of progressive MS compared to non-MS patients' normal appearing white matter (NAWM) showed induction of caspase-1 as well as other inflammasome-associated genes with concurrent suppression of neuron-specific genes. Oligodendrocytes exposed to TNFα exhibited upregulation of caspase-1 with myelin gene suppression in a cell differentiation state-dependent manner. Brains from cuprizone-exposed mice treated by intranasal delivery of the caspase-1 inhibitor, VX-765 or its vehicle, were investigated in morphological and molecular studies, as well as by fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Cuprizone exposure resulted in BMC and caspase-1 activation accompanied by demyelination and axonal injury, which was abrogated by intranasal VX-765 treatment. FDG-PET imaging revealed suppressed glucose metabolism in the thalamus, hippocampus and cortex of cuprizone-exposed mice that was restored with VX-765 treatment. These studies highlight the caspase-1 dependent interactions between inflammation, demyelination, and glucose metabolism in progressive MS and associated models. Intranasal delivery of an anti-caspase-1 therapy represents a promising therapeutic approach for progressive MS and other neuro-inflammatory diseases.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".