Therapeutic inhibition of perivascular fibroblast activity in ALS models

ALS patients have highly inconsistent life expectancy, which complicates interpretations and design of clinical trials.

This clinical variability likely represents an underlying complexity of cell type functions within the central nervous system, which modifies net survival outcomes.

We have recently discovered that perivascular fibroblasts become active before the onset of neuroinflammation and neuronal cell death in ALS and disrupt cerebral blood vessel structures (Månberg A. et al. Nature Medicine 2021).

We also showed that the increase of specific fibroblast proteins in blood plasma of ALS patients can provide a better prediction of short survival than established neurofilament biomarkers. However, the fibroblast function in the central nervous system remains poorly characterized. Our project aims to: 1.

Reduce the activity of perivascular fibroblast cells to determine their function in the nervous system.2. Inhibit the activity of fibroblast-derived SPP1 chemokine to characterize its role in neuroinflammation.  3.

Measure SPP1 protein and other vascular biomarker proteins in plasma and cerebrospinal fluid of ALS patients in order to refine the survival predictions for clinical prognosis. Our project will improve our understanding of the role of perivascular fibroblasts in the etiology of ALS.

The results could help to develop preclinical therapeutic tools to inhibit the proinflammatory SPP1 chemokine and improve prognostic accuracy of ALS patients at disease diagnosis.