Emrys Xu

Specific Degradation of Protein via an Engineering Gene Circuit 

Faculty PI: Arnab Mukherjee

Cancer is often characterized by over-expression of natural proteins. Current treatments targeting these proteins often use a cell’s natural receptors to degrade these proteins, but often fall short when the endogenous receptor’s expression level is low. To design a treatment capable of specific targeting, we introduced a modified membrane protein to the cell, aquaporin, that rapidly degrades. From here, we designed a modular bi-specific binder that can link a therapeutically-relevant protein with aquaporin. Thus, when aquaporin is degraded, the target protein is also degraded. Using a previously designed binder, we chose to target PD-L1 because it is a critical marker for immune evasion in cancer and we found that our system could degrade more than half the target protein present on the cells within 24 hours. Without a rapidly degrading aquaporin, binder-aquaporin interaction, or binder-target protein interaction, we found no significant protein degradation. With our system introducing protein instead of using an endogenous protein, we gain greater levels of control which we plan to leverage to design inducible systems to have an on/off switch for degradation. More broadly, our results also suggest the potential for a plug-and-play therapy that could ease the burden of cancer treatment on a patient’s body no matter where it's used.