Assessment of intravenous pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) in yucatan swine

PDX1 (pancreatic and duodenal homeobox 1) is overexpressed in pancreatic cancer, and its reduction results in tumor regression.Bi-functional pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) utilizes the endogenous micro-RNA biogenesis pathway to effectcleavage- and non-cleavage-dependent degradation of PDX1 mRNA. We have shown that OFHIRNA-PDX1 reduces pancreatictumor volume in xenograft models. Thus, we are now exploring biorelevant large animal safety of OFHIRNA-PDX1. Mini pigs werechosen as the biorelevant species based on the similarity of human and pig PDX1 target sequence. In the initial study, animalsdeveloped fever, lethargy, hyporexia and cutaneous hyperemia following administration of OFHIRNA-PDX1. Twenty-one days later,the same animals demonstrated less toxicity with a second OFHIRNA-PDX1 infusion in conjunction with a prophylactic regimeninvolving dexamethasone, diphenhydramine, Indocin and ranitidine. In a new group of animals, PDX1 protein (31kDa) expression inthe pancreas was significantly repressed at 48 and 72h (85%, P¼0.018 and 88%, P¼0.013; respectively) following a single infusionof OFHIRNA-PDX1 but recovered to normal state within 7 days. In conclusion, a single intravenous infusion of OFHIRNA-PDX1 inconjunction with premedication in pigs was well tolerated and demonstrated significant PDX1 knockdown.Cancer Gene Therapy (2013) 20, 683–689; doi:10.1038/cgt.2013.68; published online 29 November 2013Keywords: PDX1; RNA interference; bifunctional; pancreasINTRODUCTIONPancreatic cancer is the fourth most (in United States) and ninthmost (worldwide) cause of cancer-related deaths.