Abstract Details

Title VGL101: An Immunotherapy that Enhances Microglial Survival for Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P9 - Poster Session 9 (8:00 AM-9:00 AM)

Poster/Presentation
Number 9-013

Objective To characterize VGL101 as a high-affinity human TREM2 (hTREM2) agonistic monoclonal antibody and determine its capacity as a potential compensatory pharmacological approach to therapeutically circumvent colony-stimulating factor-1 receptor (CSF1R) dysfunction, which underlies the pathophysiology of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

Background Microglial dysregulation is broadly implicated in multiple neurodegenerative disorders and is directly causal for ALSP, a rare autosomal dominant CSF1R-related leukoencephalopathy associated with cardinal neuropathological features such as microglial loss, astrogliosis, and rapidly progressive neurodegeneration, leading to an average survival time of 6-8 years from diagnosis. Mechanistically, TREM2 and CSF1R share common microglial enrichment functions in CNS, converge on a shared intracellular signaling axis, play key roles in microglial survival, and are both established modifiers of neurodegenerative disease based on human genetic studies.

Design/Methods VGL101 effects on intracellular signaling were assessed in multiple cell-based systems to characterize TREM2-specific agonist pharmacology. To assess functional activity, human monocyte-derived macrophages (hMDMs) and stem cell?derived microglia (iMGLs) were utilized to model ALSP via CSF1R ligand withdrawal, pharmacological inhibition of CSF1R activity, and heterozygous knock-in of CSF1R^I794T. VGL101 effects were also assessed via unbiased gene expression and multiplex chemokine arrays, comparing cortical responses in hTREM2 versus TREM2 knockout mice.

Results VGL101 demonstrated specific and potent activation of downstream hTREM2 signaling. Functionally, VGL101 protected hMDMs and iMGLs from CSF1R loss-of-function, preventing microglial degeneration and preserving microglial morphology. In iMGLs harboring the risk mutant CSF1R^I794T, VGL101 similarly improved key hallmarks otherwise associated with ALSP pathology. Furthermore, transcriptomic profiling and pathway analysis in mice confirmed VGL101-induced, TREM2-dependent pharmacological activity, supporting the promising in vivo pharmacological profile for VGL101.

Conclusions These findings demonstrate VGL101 is a potent and selective TREM2 agonistic antibody, align with the hypothesis that TREM2 activation can compensate for CSF1R dysfunction, and support continued clinical development of VGL101 for the treatment of patients with ALSP.

Authors/Disclosures
Abbie Renoux (Vigil Neuroscience) PRESENTER	No disclosure on file
Kelley Larson	No disclosure on file
Frederick Gergits	No disclosure on file
	No disclosure on file
Daria Tchessalova	No disclosure on file
Borislav Dejanovic	No disclosure on file
Evan Thackaberry (Vigil Neurosciences)	Evan Thackaberry has received personal compensation for serving as an employee of Vigil Neuroscience. Evan Thackaberry has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bain Capital. Evan Thackaberry has stock in Vigil Neuroscience. Evan Thackaberry has received intellectual property interests from a discovery or technology relating to health care. Evan Thackaberry has received intellectual property interests from a discovery or technology relating to health care.
Marco Colonna (Washington University School of Medicine in Saint Louis)	No disclosure on file
David Gray (Vigil Neuroscience, Inc.)	David Gray has received personal compensation for serving as an employee of Vigil. David Gray has received personal compensation for serving as an employee of Inscopix. David Gray has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vigil. David Gray has stock in Vigil.
Christian Mirescu (Vigil Neuroscience)	No disclosure on file

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