Metabolic engineering generates a transgene-free safety switch for cell therapy

Area of Science:

• Biotechnology
• Cell Biology
• Gene Editing

Background:

• Current cell therapy safeguards rely on transgenes, posing risks like immunogenicity and silencing.
• A transgene-free control mechanism is needed to expand cell therapy applications.

Purpose of the Study:

• To engineer a novel, transgene-free safety mechanism for human cells.
• To control cell proliferation and enable selective cell elimination without transgenes.

Main Methods:

• Utilized genome editing to disrupt uridine monophosphate synthetase (UMPS) in the pyrimidine de novo synthesis pathway.
• Tested UMPS disruption in various human cell types, including cell lines, pluripotent cells, and primary T cells.
• Evaluated cell proliferation control in vitro and in vivo xenograft models by modulating external uridine supply.

Main Results:

• Disruption of UMPS rendered cell proliferation dependent on external uridine.
• Successfully controlled cell growth in vitro and in vivo by adjusting uridine availability.
• Demonstrated positive selection of UMPS-knockout cells through resistance to 5-fluoroorotic acid.

Conclusions:

• The UMPS disruption strategy offers a transgene-free method for controlling cell proliferation and enhancing safety in cell therapies.
• This approach facilitates the development of safer, potentially higher-risk cell therapies, particularly for limited treatment durations.