In JCI Insight: Clinical-grade exosomes effectively target pancreatic cancer in preclinical models
All cells release nanoscale-sized exosomes that are able to deliver DNA, RNA, proteins, and other cellular components to other cells. Due to the efficiency of delivery, exosomes are being explored for use in the delivery of therapeutic molecules. In this issue, Mayela Mendt, Sushrut Kamerkar, and colleagues describe large-scale production of Kras-targetin...g, clinical-grade exosomes (iExosomes) from bioreactor grown human mesenchymal stem/stromal cells that meet Good Manufacturing Practice (GMP) standards. iExosomes effectively targeted KrasG12D-expressing tumor cells and reduced pancreatic cancer patient-derived and orthotopic tumors in mice (see accompanying image), and prolonged survival in multiple murine pancreatic cancer models. iExosomes were well tolerated, were not immunostimulatory, and preferentially targeted tumors. Moreover, iExosomes were amenable to prolonged storage at -80oC but lost activity when left at room temperature. This report demonstrates that large-scale generation of exosomes to use in therapeutic applications is feasible and effective.
Eosinophilic esophagitis (EoE) is a chronic allergic disorder that presents with difficulty swallowing, vomiting, failure to thrive, and food impaction in adulthood. Several EoE-associated pathways have been identified; however, the underlying genetic causes of this disorder are poorly understood. In this episod...e, Marc Rothenberg and colleagues used whole-exome sequencing and identified EoE-associated variants in the mitochondrial oxioreductases DHTKD1 and OGDHL. In T cells, loss of DHTKD1 function increased ROS and viperin, which promotes Th2 cytokine production. Moreover, viperin was increased in esophageal biopsies from EoE patients. Together, these results implicate mitochondrial dysfunction in EoE pathogenesis.