Harnessing astrocyte reactivity for precision medicine in amyotrophic lateral sclerosis

ALS is a highly heterogenous motor neuron disease.

The ALS heterogeneity and consequently the challenge of patient stratification limit progress in clinical trials.Our goal is to provide new treatment strategies and biomarkers for precision medicine approach in ALS.

We hypothesize that astrocytes are key contributors to ALS heterogeneity, and that CSF biomarkers of astrocyte reactivity will aid in ALS-subtyping, allowing patient stratification for clinical trials.

We showed slower ALS progression in mice with attenuated astrocyte reactivity and identified GFAP∂ as a potential prognostic biomarker.

We discovered that C3aR modulates astrocyte reactivity, and genetic ablation of C3aR has opposite effects on ALS progression in 2 ALS mouse models.

This highlights the ALS subtype-dependent roles of C3aR and points to modulation of astrocyte reactivity as a treatment strategy for ALS.Using multiple experimental models and biobanks of ALS patient tissue and CSF, we aim to (1) identify ALS subtype-specific signatures of astrocyte reactivity and determine their utility as CSF biomarkers for patient stratification, (2) identify treatment targets and response biomarkers by characterizing the effects of genetic modulation of astrocyte reactivity and (3) determine the efficacy of experimental therapies targeting astrocyte reactivity.

The project will provide fundamental insight into ALS heterogeneity and facilitate development of personalized treatments for ALS. Time plan 2025-29.