Towards the clinical implementation of TREM2 Microglia Engineering for treating DementiaS

Introduction

TREM2MEDS emerges from the ERC PoC 2022 project TREM2μENGINES (Grant agreement ID: 101069395), which validated the efficacy of a novel treatment for Alzheimer’s Disease (AD) and Nasu-Hakola Disease (NHD) in murine models.

Background

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.

Approach

TREM2MEDS approach involves the transplantation of hematopoietic stem/progenitor cells (HSPCs) engineered by lentiviral vectors (LVs) to express robust levels of the Triggering receptor expressed on myeloid cells 2 (TREM2) in their central nervous system (CNS) myeloid/microglial progeny.

Efficacy

The engineered cells have shown the ability to:

• Reduce and prevent Aβ accumulation
• Mitigate neuroinflammation
• Restore physiological scavenging functions in the diseased CNS

These benefits have been demonstrated in robust animal models of AD and NHD.

Objectives

In TREM2MEDS, we will exploit these findings for the transition of the approach from TRL 4 to TRL 5/6 by generating IMPD-enabling data and packages. This will allow launching, at project completion, a first-in-human Phase I clinical trial of TREM2-HSPC gene therapy in AD & NHD patients carrying TREM2 hypofunctional variants.

Potential Impact

The restoration of TREM2 function in microglia, by intervening on key mechanisms contributing to neurodegeneration, has the potential to overcome the limited efficacy of current treatments for AD, which only exert symptomatic but not curative effects.

Through this work, we will thus bring to clinical testing an approach intended to become the benchmark in the treatment of AD and NHD, and possibly other dementias.