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

Cancer Gene Therapy volume 20, pages 683–689 (2013)Cite this article

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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.

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Acknowledgements

We gratefully acknowledge Bill and Olivia Heintz for their support and advice in the development of this project.

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Authors and Affiliations

  1. Gradalis, Dallas, TX, USA

    C M Jay, P Kumar, D D Rao, C Evans, Z Wang, N Senzer, J Nemunaitis & P B Maples

  2. Texas A&M Institute for Preclinical Studies, College Station, TX, USA

    C Ruoff, H Maass, B Spanhel, M Miller, A Arrington, N Montalvo, V Gresham, L King, B Weeks & T W Fossum

  3. Department of Surgery, David Geffen School of Medicine at UCLA Medical Center, Los Angeles, CA, USA

    F C Brunicardi, S-H Liu & G Zhou

  4. Mary Crowley Cancer Research Centers, Dallas, TX, USA

    N Senzer & J Nemunaitis

  5. Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, USA

    F J Clubb

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  1. C M Jay
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Correspondence to J Nemunaitis.

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Competing interests

CJ, PK, DR, CE, ZW, FCB, NS, JN and PM are shareholders in Gradalis, Inc. All the other authors declare no conflict of interest.

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Jay, C., Ruoff, C., Kumar, P. et al. Assessment of intravenous pbi-shRNA PDX1 nanoparticle (OFHIRNA-PDX1) in yucatan swine. Cancer Gene Ther 20, 683–689 (2013). https://doi.org/10.1038/cgt.2013.68

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