Loss of functional beta cell mass is a major contributor to the pathogenesis of both type 1 and type 2 diabetes. Enhancing proliferation of existing beta cells in the pancreatic islet is one of the promising approaches for restoring functional beta cell mass. Increasing evidence indicates inhibition of dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1a) stimulates beta cell proliferation. However, to date DYRK1a small molecule inhibitors have not been therapeutically viable due to their ability to increase proliferation in peripheral tissues. Previously we demonstrated that generation 2.5 antisense oligonucleotides (ASO) conjugated to a glucagon like peptide 1 receptor (GLP-1R) agonist can specifically target the pancreatic beta cell. When compared to control ASO treated isolated islets, islets administered a GLP-1/Dyrk1a ASO conjugate reduces DYRK1a mRNA and protein expression and significantly increases Ki67 mRNA, a cell proliferation marker, in a dose-response manner in vitro. Furthermore, combination treatment of a GLP-1/Dyrk1a ASO conjugate and the small molecule TGF-β inhibitor Ly364947, can synergistically increase Ki67 mRNA expression, cell cycle progression markers cyclin D1, cyclin E2, Cdk1, Cdk4 mRNAs and beta cell markers Pdx1 and Glut2 mRNAs when compared to a DYRK1a conjugated ASO or Ly364947 alone. Administration of a Dyrk1a conjugated ASO to wild type and db/db mice reduced Dyrk1a mRNA and increased Ki67 mRNA expression in islets when compared to a control ASO. Cell cycle markers cyclin D2, cyclin E2 and Cdk1 mRNAs are also significantly upregulated.
In conclusion, a GLP-1/Dyrk1a ASO conjugate can specifically inhibit beta cell Dyrk1a mRNA expression and promote beta cell proliferation, suggesting that this may be an important approach for the treatment of type 1 and type 2 diabetes.
W. Fu: Employee; Self; Ionis Pharmaceuticals, Inc. R. Lee: Employee; Self; Ionis Pharmaceuticals, Inc. E.C. Pirie: Employee; Self; Ionis Pharmaceuticals, Inc. T. Prakash: None. S. Murray: Employee; Self; Ionis Pharmaceuticals. A. Powers: Employee; Self; Ionis Pharmaceuticals, Inc. Stock/Shareholder; Self; Ionis Pharmaceuticals, Inc. A.E. Mullick: None. R.M. Crooke: Employee; Self; Ionis Pharmaceuticals, Inc. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc.