title: Assessment of intravenous pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) in yucatan swine.
abstract: 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 effect cleavage- and non-cleavage-dependent degradation of PDX1 mRNA. We have shown that OFHIRNA-PDX1 reduces pancreatic tumor volume in xenograft models. Thus, we are now exploring biorelevant large animal safety of OFHIRNA-PDX1. Mini pigs were chosen as the biorelevant species based on the similarity of human and pig PDX1 target sequence. In the initial study, animals developed 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 regimen involving dexamethasone, diphenhydramine, Indocin and ranitidine. In a new group of animals, PDX1 protein (31 kDa) expression in the pancreas was significantly repressed at 48 and 72 h (85%, P=0.018 and 88%, P=0.013; respectively) following a single infusion of OFHIRNA-PDX1 but recovered to normal state within 7 days. In conclusion, a single intravenous infusion of OFHIRNA-PDX1 in conjunction with premedication in pigs was well tolerated and demonstrated significant PDX1 knockdown.
authors.affiliation: Gradalis, Dallas, TX, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Jay
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ruoff
authors.affiliation: Gradalis, Dallas, TX, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Maass
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Spanhel
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Miller
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Arrington
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Montalvo
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Gresham
authors.affiliation: Gradalis, Dallas, TX, USA.
authors.forename: D D
authors.initials: DD
authors.lastname: Rao
authors.affiliation: Gradalis, Dallas, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Evans
authors.affiliation: Gradalis, Dallas, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA Medical Center, Los Angeles, CA, USA.
authors.forename: F C
authors.initials: FC
authors.lastname: Brunicardi
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA Medical Center, Los Angeles, CA, USA.
authors.forename: S-H
authors.initials: SH
authors.lastname: Liu
authors.affiliation: Department of Surgery, David Geffen School of Medicine at UCLA Medical Center, Los Angeles, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.affiliation: 1] Gradalis, Dallas, TX, USA [2] Mary Crowley Cancer Research Centers, Dallas, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Senzer
authors.affiliation: 1] Gradalis, Dallas, TX, USA [2] Mary Crowley Cancer Research Centers, Dallas, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nemunaitis
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: King
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Weeks
authors.affiliation: Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, USA.
authors.forename: F J
authors.initials: FJ
authors.lastname: Clubb
authors.affiliation: Texas A&M Institute for Preclinical Studies, College Station, TX, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Fossum
authors.affiliation: Gradalis, Dallas, TX, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Maples
mesh_terms: D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D001786:Blood Glucose; D001831:Body Temperature; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D051379:Mice; D058726:Nanoconjugates / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D010957:Plasmids / Q000737:chemistry / Q000235:genetics; D020033:Protein Isoforms; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013552:Swine; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D058726:Nanoconjugates; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein