VGL101 Rescues CSF1R Dysfunction in Human Microglia And Macrophages: Evaluation of In Vitro Trem2 Agonism in Models Of A CSF1R‐Dependent Leukodystrophy

Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal dominant primary microgliopathy caused by kinase loss‐of‐function mutations in the CSF1 receptor (CSF1R). The cardinal features of ALSP include demyelination, axonopathy, and symptoms ranging from frontal temporal dementia‐like behavior, movement disorders, epilepsy, and psychiatric manifestations. Many of these hallmarks further resemble Nasu‐Hakola disease, another rare leukoencephalopathy associated with homozygous mutations in triggering receptor expressed on myeloid cells 2 (TREM2) or its tyrosine kinase binding adaptor (TYROBP) which result in complete loss‐of‐function of TREM2 or its signaling partner DAP12. Following binding to its cognate ligands, IL‐34 or CSF‐1, CSF1R dimerization initiates a signaling cascade both through its kinase domain and through DAP12, which together activate SYK to promote myeloid cell survival, proliferation, and morphological changes. While analogous to CSF1R in cellular expression and interaction with DAP12, TREM2 lacks intrinsic signaling capacity and therefore requires DAP12 to translate extracellular damage‐associated cues and orchestrate a constellation of intracellular and functional responses which phenocopy CSF1R activation. Accordingly, we hypothesize TREM2 activation may rescue CSF1R loss‐of‐function and ameliorate ALSP‐associated pathology.