title: Gene therapy with neurogenin3, betacellulin and SOCS1 reverses diabetes in NOD mice.
abstract: Islet transplantation for type 1 diabetes is limited by a shortage of donor islets and requirement for immunosuppression. We approached this problem by inducing in vivo islet neogenesis in non-obese diabetic (NOD) diabetic mice, a model of autoimmune diabetes. We demonstrate that gene therapy with helper-dependent adenovirus carrying neurogenin3 (Ngn3), an islet lineage-defining transcription factor, and betacellulin (Btc), an islet growth factor, leads to the induction of periportal insulin-positive cell clusters in the liver, which are rapidly destroyed. To specifically accord protection to these 'neo-islets' from cytokine-mediated destruction, we overexpressed suppressor of cytokine signaling 1 (SOCS1) gene, using a rat insulin promoter in combination with Ngn3 and Btc. With this approach, about half of diabetic mice attained euglycemia sustained for over 4 months, regain glucose tolerance and appropriate glucose-stimulated insulin secretion. Histological analysis revealed periportal islet hormone-expressing 'neo-islets' in treated mouse livers. Despite evidence of persistent 'insulitis' with activated T cells, these 'neo-islets' persist to maintain euglycemia. This therapy does not affect diabetogenicity of splenocytes, as they retain the ability to transfer diabetes. This study thus provides a proof-of-concept for engineering in vivo islet neogenesis with targeted resistance to cytokine-mediated destruction to provide a long-term reversal of diabetes in NOD mice.
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Buras
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Liu
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Espiritu
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ozer
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Thompson
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Nally
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Yuan
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Oka
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Chang
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Samson
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Yechoor
authors.affiliation: DRC and Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chan
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D066259:Betacellulin / Q000096:biosynthesis / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007165:Immunosuppression Therapy; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics; D007515:Islets of Langerhans / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000379:methods; D008099:Liver / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D066259:Betacellulin; D007328:Insulin; D009419:Nerve Tissue Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C407737:Neurog3 protein, mouse; C491590:Socs1 protein, mouse