TREM2 MICROglia ENGENEering for treating dementiaS (TREM2MICROENGINES)

Introduction

The project TREM2MICROENGINES aims at demonstrating that raising and restoring TREM2 expression in the brain of Alzheimer’s disease (AD) and Nasu–Hakola disease (NHD) patients, and in particular in their microglia, would result in therapeutic benefit.

Alzheimer’s Disease Overview

AD is a severe neurodegenerative disorder that represents the most frequent form of dementia among the elderly, affecting approximately 5.1 million Americans. This number is supposedly tripled by 2050.

AD is believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques.

TREM2 and Microglial Dysfunction

TREM2 (Triggering receptor expressed on myeloid cells 2) is a microglia cell-surface receptor whose deficiency or haplo-insufficiency augments Aβ accumulation due to a dysfunctional response of cells, which become apoptotic.

Homozygous, loss-of-function mutations in TREM2 also cause the autosomal recessive disorder NHD, an ultra-rare inherited disease of the white matter (WM) with typical onset in adulthood.

NHD is patho-physiologically characterized by microglial dysfunction (microgliopathy). The key clinical feature of NHD is progressive presenile dementia, usually leading to death in the fifth decade of life.

NHD patients also lack curative treatments. A relevant proportion of AD cases and all forms of NHD are caused by pathogenic mutations in the Trem2 gene, which lead to microglia dysfunction contributing to and/or causing the onset and manifestations of AD and NHD.

Working Hypothesis

Based on this provision, our working hypothesis is that:

1. Transplantation of HSCs engineered by LVs to express robust TREM2 levels in response to tissue damage in CNS-engrafted myeloid/microglia cells would:
   • Modulate neuroinflammation
   • Restore physiological microglia functions
   • Contribute to preventing and reducing Aβ accumulation in the CNS of AD and NHD patients.

Current Limitations

No existing approaches currently allow targeting microglia dysfunction in AD or in NHD, nor enhancing microglia-specific function through a microglia-targeted TREM2 delivery/engineering.