Rewiring gene regulatory circuits to enhance central nervous system repair

Projektinformationen

EnhanceRegen

ID Finanzhilfevereinbarung: 101078168

DOI

10.3030/101078168

EK-Unterschriftsdatum 20 Dezember 2022

Startdatum 1 Mai 2023

Enddatum 30 April 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 500 000,00

EU-Beitrag

€ 1 500 000,00

Koordiniert durch

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 1 - EnhanceRegen (Rewiring gene regulatory circuits to enhance central nervous system repair)

Berichtszeitraum: 2023-05-01 bis 2025-10-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

When the central nervous system (CNS) is injured, unlike other parts of our body, it cannot repair itself. This leads to permanent disabilities that cause immense personal suffering and represent a growing global health burden. Interestingly, some animals like fish and salamanders can completely regenerate their spinal cords after injury, restoring both the cellular architecture and full function. The key difference lies in how their cells respond to injury, a response program encoded in their DNA.

In mammals, neural stem cells exist in the CNS and can proliferate after injury, but they lack access to the right genetic programs needed for true regeneration. Instead, they form scar tissue with minimal contribution to replacing lost neurons and other brain cells. The problem is that mammalian cells have lost the regulatory "instructions" that would tell them how to reactivate developmental programs upon injury.

The overall objective of EnhanceRegen is to solve this problem by designing synthetic DNA regulatory elements called enhancers. These enhancers act like molecular switches that can sense injury and then activate the right genes to unlock the dormant regenerative potential of resident neural stem cells.
Rather than relying on risky cell transplantation approaches, this project aims to "hack" the body's own repair mechanisms to achieve CNS regeneration.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

EnhanceRegen has systematically mapped how injury-induced gene expression programs are encoded in the mammalian CNS.
Using cutting-edge genomics technologies, we identified thousands of injury-responsive enhancers in the mouse spinal cord and discovered that these are particularly abundant in glial cells. Importantly, these enhancers maintain their cell type specificity even when controlling shared injury response genes.
Through AI approaches applied to DNA sequences, we decoded the architectural principles underlying these enhancers, revealing that they integrate generic injury-sensing elements with cell identity programs to achieve precise targeting. We demonstrated that injury-responsive enhancers can selectively target reactive cells at injury sites using clinically relevant gene delivery methods. This work has provided fundamental insights into how the genome encodes injury-responsive gene expression and established the feasibility of using synthetic enhancers for therapeutic targeting of specific cell states in the injured CNS.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

Our results enable the AI-guided design of synthetic enhancers that can selectively target injury-responsive cell states in the CNS. This approach could complement existing cell replacement strategies by potentially activating endogenous repair mechanisms. The ability to program enhancers for specific cellular targeting may have applications in treating spinal cord injuries and other CNS disorders, offering a foundation for developing more precise gene therapy approaches with reduced reliance on cell transplantation.