Dissecting innate immune BarRiers and nucleic Acid ImmuNitY to advance CNS-targeted therapies
| Title | Dissecting innate immune BarRiers and nucleic Acid ImmuNitY to advance CNS-targeted therapies |
|---|---|
| Acronym | BRAINY |
| Start date | 2026-11-01 |
| End date | 2031-09-30 |
| Sponsor | European Research Council - Advanced Grant (ERC-AdG) |
| Institution | University of Pavia-Department of Biology and Biotechnology |
Associated cell lines
Project Description
Adeno-Associated Virus (AAV) vector-based gene therapies targeting the central nervous system (CNS) hold tremendous potential to treat a broad range of neurological disorders. Nevertheless, suboptimal efficacy and severe adverse events with unclear mechanistic basis encountered in recent clinical trials are hampering their successful implementation. While most research addressing these issues is centred on vector engineering and adaptive immunity, my team has pioneered the study of cell-intrinsic innate immunity in the context of ex vivo gene therapies. We discovered that innate sensing of viral vectors affects target cell biology, identified antiviral factors potently blocking gene transfer and developed methods that overcome them. However, the molecular mechanisms of these innate immune barriers and their impact on gene therapies remain unexplored in the human CNS. Our recent findings reveal that AAVs trigger neurotoxic innate immune signalling in advanced human pluripotent stem cell-derived models of the human CNS as well as in vivo in mice and that type I IFN-induced factors limit transduction in CNS cells. Here, we aim to 1) dissect the CNS-specific mechanisms of innate immune sensing of AAV gene delivery, 2) identify antiviral restriction blocks hampering efficient AAV transduction in CNS cells, and 3) develop improved CNS-targeting gene engineering strategies. We will combine in vitro human CNS and in vivo mouse models with advanced molecular virology tools, CRISPR screens, omics technologies and hypothesis-driven approaches in a broad program designed to balance high-risk/high-gain with low-risk/high-gain tasks. Together, our efforts go beyond the state-of-the-art and will address key knowledge gaps in CNS-specific innate immune responses to pioneer the development of cutting-edge gene therapies in the human nervous system. BRAINY builds on the unique cross disciplinary expertise of the PI, strategically positioned to make paradigm-changing discoveries.