title: Establishing a Large-Animal Model for In Vivo Reprogramming of Bile Duct Cells into Insulin-Secreting Cells to Treat Diabetes.
abstract: Type 1 diabetes manifests as autoimmune destruction of beta cells requiring metabolic management with an exogenous replacement of insulin, either by repeated injection of recombinant insulin or by transplantation of allogeneic islets from cadaveric donors. Both of these approaches have severe limitations. Repeated insulin injection requires intensive blood glucose monitoring, is expensive, and is associated with decreased quality-of-life measures. Islet transplantation, while highly effective, is severely limited by shortage of donor organs. Clinical translation of beta cells derived from pluripotent stem cells is also not yet a reality, and alternative approaches to solving the replacement of lost beta cell function are required. In vivo direct reprogramming offers an attractive approach to generating new endogenous insulin-secreting cells by permanently altering the phenotype of somatic cells after transient expression of transcription factors. Previously, we have successfully restored control of blood glucose in diabetic mice by reprogramming liver cells into glucose-sensitive insulin-secreting cells after the transient, simultaneous delivery of three transcription factors (Pdx1, Ngn3, and MafA) to the liver of diabetic mice, using an adenoviral vector (Ad-PNM). Establishing a clinically relevant, large-animal model is a critical next step in translating this approach beyond the proof-of-principle stage in rodents and allowing investigation of vector design, dose and delivery, host response to vector infusion, and establishment of suitable criteria for measuring safety and efficacy. In this feasibility study we infused Ad-PNM into the liver of three diabetic cynomolgus macaques via portal vein catheter. Vector presence and cargo gene and protein expression were detected in liver tissue after infusion with no adverse effects. Refinement of immune suppression significantly extended the period of exogenous PNM expression. This pilot study establishes the suitability of this large-animal model to examine the translation of this approach for treating diabetes.
authors.affiliation: 1 Stem Cell Institute, McGuire Translational Research Facility, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Hill
authors.affiliation: 1 Stem Cell Institute, McGuire Translational Research Facility, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Anannya
authors.initials: A
authors.lastname: Banga
authors.affiliation: 2 University of Minnesota Informatics Institute, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Juan E
authors.initials: JE
authors.lastname: Abrahante
authors.affiliation: 1 Stem Cell Institute, McGuire Translational Research Facility, University of Minnesota , Minneapolis, Minnesota.|5 Bioinformatics and Computational Biology Program, University of Minnesota , Rochester, Minnesota.
authors.forename: Ce
authors.initials: C
authors.lastname: Yuan
authors.affiliation: 3 Department of Surgery, Preclinical Research Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Mutch
authors.affiliation: 3 Department of Surgery, Preclinical Research Center, University of Minnesota , Minneapolis, Minnesota.
authors.forename: Jody
authors.initials: J
authors.lastname: Janecek
authors.affiliation: 1 Stem Cell Institute, McGuire Translational Research Facility, University of Minnesota , Minneapolis, Minnesota.|4 Department of Veterinary Population Medicine, University of Minnesota , St. Paul, Minnesota.
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: 3 Department of Surgery, Preclinical Research Center, University of Minnesota , Minneapolis, Minnesota.|4 Department of Veterinary Population Medicine, University of Minnesota , St. Paul, Minnesota.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Graham
authors.affiliation: 1 Stem Cell Institute, McGuire Translational Research Facility, University of Minnesota , Minneapolis, Minnesota.
authors.forename: James R
authors.initials: JR
authors.lastname: Dutton
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000166:cytology* / Q000378:metabolism; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D000229:Dependovirus / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D010865:Pilot Projects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: diabetes; nonhuman primate; reprogramming