Periodic Reporting for period 1 - TREM2MEDS (Towards the clinical implementation of TREM2 Microglia Engineering for treating DementiaS)
Berichtszeitraum: 2024-04-01 bis 2025-03-31
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. 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. 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. The engineered cells have shown the ability to reduce and prevent Aβ accumulation, mitigate neuroinflammation and restore physiological scavenging functions in the diseased CNS, benefiting AD and NHD in robust animal models. In TREM2MEDS, we will exploit these findings for transition of the approach from TRL 4 to TRL 5/6 by generating IMPD-enabling data and packages that 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. 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.
In TREM2MEDS, we aim to advance the proof of concept we recently generated (Milazzo et al., Nat COmm 2024) towards its clinical implementation. To this goal, we will combine i) a reduced intensity conditioning regime compatible with robust microglia replacement by the TREM2 engineered cells and with the safe treatment of AD (and NHD) patients; and ii) innovative and advanced protocols for LV and cell manufacturing in clinical grade conditions developed by INSERM for clinical translation, with the funding elements that allowed our strategy to be thus uniquely successful, namely iii) the novel and IP-protected delivery route in the brain lateral ventricles that we pioneered, allowing selective and exclusive CNS engraftment of the engineered HSPCs and their differentiation in bona fide microglia (developed in a previous ERC CoG grant [9,19]); iv) the expression of TREM2 as a therapeutic molecule to restore a functional microglia population in the CNS of AD and NDH; v) a newly developed and IP protected synthetic promoter we designed based on the HLA-DRA gene promoter (Ciervo et al., under peer revision; WO2022234445 patent) that would allow TREM2 expression in transplant-derived microglia-like cells in response to (neuro)inflammation (tested in the PoC ERC). Combining these concepts in the proposed strategy will render the approach not only highly innovative, but also endowed with great therapeutic potential for benefiting AD and NHD patients and highly competitive.
In TREM2MEDS, we aim to advance the proof of concept we recently generated (Milazzo et al., Nat COmm 2024) towards its clinical implementation. To this goal, we will combine i) a reduced intensity conditioning regime compatible with robust microglia replacement by the TREM2 engineered cells and with the safe treatment of AD (and NHD) patients; and ii) innovative and advanced protocols for LV and cell manufacturing in clinical grade conditions developed by INSERM for clinical translation, with the funding elements that allowed our strategy to be thus uniquely successful, namely iii) the novel and IP-protected delivery route in the brain lateral ventricles that we pioneered, allowing selective and exclusive CNS engraftment of the engineered HSPCs and their differentiation in bona fide microglia (developed in a previous ERC CoG grant [9,19]); iv) the expression of TREM2 as a therapeutic molecule to restore a functional microglia population in the CNS of AD and NDH; v) a newly developed and IP protected synthetic promoter we designed based on the HLA-DRA gene promoter (Ciervo et al., under peer revision; WO2022234445 patent) that would allow TREM2 expression in transplant-derived microglia-like cells in response to (neuro)inflammation (tested in the PoC ERC). Combining these concepts in the proposed strategy will render the approach not only highly innovative, but also endowed with great therapeutic potential for benefiting AD and NHD patients and highly competitive.
TREM2MEDS reports significant progress in advancing the TREM2-HSPC gene therapy approach from TRL 4 toward TRL 5/6, in line with the objectives outlined in the Proposal. As a first step, all key preparatory activities essential for the successful implementation of TREM2MEDS have been completed. This includes activating the working groups both internally (at UNIPD, UNISMART, IMG, and INSERM) and across partner institutions, assignment of tasks, establishment of recurring monthly operational meetings, and drafting of study protocols along with the necessary SOPs. Additionally, all required documentation at due stage has been prepared and submitted for approval by the relevant authorities to obtain authorization for animal testing, ensuring readiness to initiate in vivo experimental activities.
Subsequently, UNIPD has completed Task1.1 – Reduced conditioning regime testing. Briefly, data have been generated to support the use of a novel reduced intensity conditioning regime that allows for a sustained transduced cell engraftment within the myeloid/microglia brain compartment. This regime of low intensity conditioning will thus be exploited in the subsequent tasks. In parallel, INSERM led activities under Task 2.1. Working closely with UNIPD, INSERM has sequenced, annotated, produced and quality-controlled the TREM2_LV lentiviral gene transfer plasmid and implemented a clinically-applicable protocol for the production of the TREM2_LV, with production of research-grade and medium scale preparations. In preparation for Task 2.2 - In vivo biodistribution and safety/toxicology testing, IMG worked closely with UNIPD and INSERM to set up for GLP studies that are planned to commence on M18. To ensure a smooth transition toward clinical translation, a regulatory specialist has been involved in the relevant working groups from the outset of the TREM2MEDS project. This early involvement provides guidance on technical, CMC, and scientific aspects, ensuring that the generated data comply with EMA and FDA regulatory requirements and can be used for IMPD applications. UNIPD has also begun working on the identification of experts to be enrolled in Clinical ADvisory Board activities, in line with the expected timelines.
TREM2MEDS, thus, remains on track, supporting the continued development of the TREM2-HSPC gene therapy in line with the Project Proposal and progressing.
Subsequently, UNIPD has completed Task1.1 – Reduced conditioning regime testing. Briefly, data have been generated to support the use of a novel reduced intensity conditioning regime that allows for a sustained transduced cell engraftment within the myeloid/microglia brain compartment. This regime of low intensity conditioning will thus be exploited in the subsequent tasks. In parallel, INSERM led activities under Task 2.1. Working closely with UNIPD, INSERM has sequenced, annotated, produced and quality-controlled the TREM2_LV lentiviral gene transfer plasmid and implemented a clinically-applicable protocol for the production of the TREM2_LV, with production of research-grade and medium scale preparations. In preparation for Task 2.2 - In vivo biodistribution and safety/toxicology testing, IMG worked closely with UNIPD and INSERM to set up for GLP studies that are planned to commence on M18. To ensure a smooth transition toward clinical translation, a regulatory specialist has been involved in the relevant working groups from the outset of the TREM2MEDS project. This early involvement provides guidance on technical, CMC, and scientific aspects, ensuring that the generated data comply with EMA and FDA regulatory requirements and can be used for IMPD applications. UNIPD has also begun working on the identification of experts to be enrolled in Clinical ADvisory Board activities, in line with the expected timelines.
TREM2MEDS, thus, remains on track, supporting the continued development of the TREM2-HSPC gene therapy in line with the Project Proposal and progressing.
TREM2MEDS thus far has generated new information regarding both the efficacy of TREM2-transduced HSPC gene therapy in relevant disease animal models and the mechanisms by which this treatment approach ameliorates the disease features (Ciervo et al., in preparation). Moreover, it established a new method for enabling a robust engraftment of transplant-derived microglia in the CNS based on a reduced intensity conditioning regime (patent application in preparation).