Exosome platform for tissue-specific drug delivery of mRNA or other therapeutic cargo

Researchers in Prof. A.C. Matin's laboratory have developed a versatile exosome (extracellular vesicle, "EV") drug delivery platform that can selectively target therapeutic agents to tumors or other tissues that overexpress extracellular receptors. This technology, called “EXO-DEPT” (exosome-directed enzyme prodrug therapy), directs therapeutic agents to the disease tissue while minimizing effects on healthy tissue by utilizing high-affinity ligands tethered to exosomes. This specificity allows higher concentrations of toxic drugs to be confined to a target/tumor site while preventing damage and severe side effects elsewhere. This may also decrease the risk drug resistance. EXO-DEPT was demonstrated by delivering functional exogenous mRNA to in HER2 positive breast cancer cells, thereby converting a harmless prodrug to a highly toxic drug that arrested tumor growth in mice. The basic system could also be adapted for a range of cargo molecules (e.g., siRNA, DNA, proteins or small molecule drugs) and receptor targets (e.g., PSMA, bombasin, folate, transferrin and sigma). Moreover, as exosomes can cross the blood brain barrier, this technology can treat metastasized cancer to the brain (often the case with breast and other cancers) as well as neurological diseases, such as Alzheinmer's.

Stage of Research
The inventors have demonstrated that the EXO-DEPT system with a high affinity anti-HER2 antibody can specifically deliver mRNA cargo to HER2 positive cells. Furthermore, they have shown that the functional mRNA delivered to the tumor cells converts a prodrug (CHOB) into a highly toxic drug (MCHB) which completely arrests tumor growth in a mouse model of HER2 positive breast cancer. This is the first demonstration of EV-mediated delivery of functional exogenous mRNA to tumors. The inventors continue to enhance the therapy and have a program to utilize the platform in treating metastatic brain tumors.

Figures:

Description: Treatment of implanted orthotopic HER2 positive breast cancer in mice. Note that while controls show continued tumor growth, mice treated with EXO-DEPTs + the prodrug show complete arrest of tumor development.