Safeguard Repressor-Mediated Cell Fate Lock Gene Therapy for Glioblastoma

Cel

"Glioblastoma (GBM) remains the most lethal primary brain tumour, with a median survival of 15 months despite maximal treatment, unchanged in two decades. Over 95% of clinical trials have failed. The fundamental reason is cell fate plasticity: GBM cells switch between phenotypic states to evade any single therapy. No current approach addresses the regulatory machinery that permits this switching.

SafeCure will translate two discoveries from ERC Starting Grant SafeFate into a first-in-class gene therapy. The first is MYT1L, a neuronal transcription factor we identified as a ""safeguard repressor"" that locks GBM cells in a stable, low-plasticity state by suppressing alternative fate programmes. In orthotopic mouse models that faithfully recapitulate human GBM, MYT1L already extends survival significantly as monotherapy. To achieve safe, targeted re-expression of MYT1L exclusively in tumour cells, we developed a second innovation: 96 tumour-specific enhancers (TSEs) identified through our AI framework (scDORI), which drive gene expression in GBM cells while remaining silent in healthy brain. Delivered via adeno-associated virus (AAV) and combined with standard chemotherapy, this creates a ""lock-and-kill"" strategy: MYT1L locks cells in a vulnerable state; chemotherapy and radiotherapy kill them.

SafeCure comprises three goals: engineering and validation of AAV-TSE-MYT1L therapeutic constructs; preclinical proof-of-concept with survival, cell fate, and safety endpoints; IP strategy, regulatory pre-assessment, and industry engagement. Two patent families with established priority dates secure the core technology. The project will deliver an investor-ready preclinical package positioning SafeCure for translational funding and first-in-human translation."