Descrizione del progetto
Un approccio di biologia sintetica nell’immunoterapia con cellule T
Negli ultimi anni, le immunoterapie basate su cellule hanno goduto di un notevole successo clinico. Tuttavia, i vantaggi a lungo termine sono spesso compromessi da disfunzioni delle cellule T in conseguenza dell’esposizione a un antigene cronico, un processo noto come esaurimento delle cellule T. I trattamenti attuali dell’esaurimento delle cellule T sono limitati e comportano effetti avversi. Il progetto Synthetic T-rEX, finanziato dall’UE, si propone di sviluppare una strategia per riprogrammare le cellule T esauste utilizzando circuiti di biologia sintetica. Il progetto costruirà circuiti genetici specifici e autonomi con parametri migliori per ridurre al minimo l’impatto sulla normale fisiologia cellulare, intervenendo sui segnali intracellulari esaurimento-specifici per ristabilire l’attività delle cellule T e per ripristinare la normale funzione immunitaria. I circuiti genetici saranno sviluppati sulla base dell’identificazione di modifiche esaurimento-specifiche dall’RNA e da profili di sequenziamento di microRNA da cellule T CD8+ umane esauste ex vivo.
Obiettivo
Synthetic Biology has revolutionised approaches for several scientific, industrial and medical applications. These include the development of immunotherapies based on bioengineered cells, most notably engineering of patients T cells with tumor-targeting receptors, the CAR-T cells. Cell-based immunotherapies have shown remarkable clinical success; yet, long-term benefits are hampered by dysfunction of T cells occurring following antigen chronic exposure, a process known as T cell exhaustion. Current treatments of T cell exhaustion are limited and exhibit adverse effects.
Synthetic T-rEX aims to reprogram exhausted T-cells using synthetic biology circuits, to implement enhanced and more effective immune cell-based therapies. We will develop specific, self-contained genetic circuits with improved capabilities that minimise the impact on normal cell physiology; by pre-programmed integration of exhaustion-specific intracellular signals, these will rewire T cell activity and restore normal function. Circuits will be developed using a stepwise, bottom-up approach to identify exhaustion-specific inputs by RNA and microRNA-sequencing profile performed on ex vivo exhausted human CD8+ T cells. We will then design (a) synthetic promoters and (b) microRNA-regulated 5’UTR that will compute information processing to trigger output activation. Localised therapy will rely on concerted action of genetically encoded immune-checkpoint blockade and fine-tuning of epigenetic modulators that play a major role in T cell exhaustion. Finally, we will engineer T cells with sensor-actuator synthetic devices that revert exhaustion (T-rEX cells). In summary, our proposal provides a paradigm shift in the development of strategies against T cell exhaustion and a solid break-through towards enhanced natural and cell-based immunotherapy. More broadly, the proposed approach will unleash the potential of synthetic biology to the next level of therapeutic intervention.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
16163 Genova
Italia