Drug Development

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Microglia are key innate immune cells in the brain, crucial for maintaining health and resolving Alzheimer's Disease (AD) pathology.
• TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is a receptor that modulates microglia responses to misfolded proteins, essential for neuronal function.
• MTX46943 is a novel, potent, selective, safe, and brain-penetrant small molecule agonist targeting TREM2 for early AD treatment.

Purpose of the Study:

• To investigate the mechanism of action and efficacy of MTX46943, a TREM2 agonist, in activating microglia and reducing AD pathology.
• To characterize the downstream effects of MTX46943 on TREM2 receptor complex dynamics and microglia function.
• To evaluate the in vivo impact of chronic MTX46943 treatment on amyloid pathology in a mouse model of AD.

Main Methods:

• In vitro assays (nanoBiT, Western blot, alphaLISA, migration, phagocytosis) were used to assess TREM2 activation and downstream effects in various cell types.
• Comparison of MTX46943 with TREM2 agonist antibodies to differentiate receptor activation modalities.
• In vivo studies involved chronic treatment of 5xFAD // hTREM2 knock-in mice, followed by analysis of microglia and brain tissue using qPCR, single-cell RNA sequencing, and immunostaining.

Main Results:

• MTX46943 promotes TREM2/DAP12 receptor complex formation and stabilizes its surface presence, crucial for microglia activation, distinct from antibody agonists.
• In vivo, MTX46943 treatment reprogrammed microglia in the presence of amyloid pathology, leading to a significant reduction in neurotoxic amyloid beta species.
• Observed effects in vivo were consistent with MTX46943's in vitro potency at brain-penetrant exposure levels.

Conclusions:

• MTX46943, a selective TREM2 agonist, is advancing to clinical studies for early Alzheimer's Disease treatment.
• The study demonstrates MTX46943's differentiated mechanism involving TREM2 receptor complex stabilization and microglia reprogramming.
• Chronic MTX46943 treatment significantly reduces brain amyloid pathology and supports its potential as a best-in-class therapy for AD.