title: dsAAV8-mediated gene transfer and β-cell expression of IL-4 and β-cell growth factors are capable of reversing early-onset diabetes in NOD mice.
abstract: Type-I diabetes is a chronic disease mediated by autoimmune destruction of insulin-producing β-cells. Although progress has been made towards improving diabetes-associated pathologies and the quality of life for those living with diabetes, no therapy has been effective at eliminating disease manifestations or reversing disease progression. Here, we examined whether double-stranded adeno-associated virus serotype 8 (dsAAV8)-mediated gene delivery to endogenous β-cells of interleukin (IL)-4 in combination with β-cell growth factors can reverse early-onset diabetes in NOD mice. Our results demonstrate that a single treatment with dsAAV8 vectors expressing IL-4 in combination with glucagon-like peptide-1 or hepatocyte growth factor/NK1 under the regulation of the insulin promoter enhanced β-cell proliferation and survival in vivo, significantly delaying diabetes progression in NOD mice, and reversing disease in ∼10% of treated NOD mice. These results demonstrate the ability to reverse hyperglycemia in NOD mice with established diabetes by in vivo gene transfer to β-cells of immunomodulatory factors and β-cell growth factors.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Gaddy
authors.forename: M J
authors.initials: MJ
authors.lastname: Riedel
authors.forename: S
authors.initials: S
authors.lastname: Bertera
authors.forename: T J
authors.initials: TJ
authors.lastname: Kieffer
authors.forename: P D
authors.initials: PD
authors.lastname: Robbins
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000628:therapy*; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D015847:Interleukin-4; D017228:Hepatocyte Growth Factor; D052216:Glucagon-Like Peptide 1