2143-P: GLP-1 Conjugation Enhances the Activity of Antisense Oligonucleotides Targeting Islet Amyloid Polypeptide (IAPP) or Kelch-Like ECH Associated Protein 1 (Keap1) in Isolated Pancreatic Islets

Abstract

The incidence of type 2 diabetes (T2D) is increasing rapidly and is currently one of the 21st century’s major challenges to human health. While T2D has a complex etiology, beta cell dysfunction is widely regarded as a key contributor to T2D disease progression. Antisense oligonucleotides (ASOs) have been shown to provide substantial therapeutic benefit for numerous unmet medical needs. However, unconjugated ASOs have shown minimal activity in pancreatic beta cells, limiting their use as therapeutics in these cells. It has recently been shown that conjugation of glucagon like peptide 1 receptor (GLP-1R) ligands (GLP-1R-L) to ASOs led to significant, substantial increases of ASO activity in the pancreatic islet beta cell, making them a viable therapeutic option for treatment of beta cell dysfunction.1 Two factors that contribute to beta cell dysfunction are IAPP and oxidative stress. A key inhibitor of the intracellular anti-oxidative response is Keap1. We treated isolated islets with parent or GLP-1R-L conjugated ASOs targeting either Keap1 or IAPP. At the highest dose, the parent ASOs reduced their respective islet target mRNAs by up to 20%, while the GLP-1 conjugated ASOs reduced target mRNA by 85%-95%. Furthermore, the GLP-1R-L conjugated Keap1 ASO treatment increased mRNA expression of the anti-oxidative response gene NAD(P)H quinone dehydrogenase 1 (Nqo1) by 390% when compared to PBS controls. Systemic treatment of C57BL/6 mice with the GLP-1R-L conjugated IAPP ASO reduced islet IAPP mRNA by 79% ± 3.7% when compared to saline treated animals. These data suggest that GLP-1R-L conjugated ASOs show exciting potential as a therapeutic platform for the treatment of beta cell dysfunction. Disclosure W. Fu: None. R. Lee: Employee; Self; Ionis Pharmaceuticals, Inc. E.C. Pirie: Employee; Self; Ionis Pharmaceuticals, Inc. T. Prakash: Employee; Self; Ionis Pharmaceuticals, Inc. S. Murray: Employee; Self; Ionis Pharmaceuticals, Inc. A.F. Powers: Employee; Self; Ionis Pharmaceuticals, Inc. Stock/Shareholder; Self; Ionis Pharmaceuticals, Inc. R.M. Crooke: Employee; Self; Ionis Pharmaceuticals, Inc. Employee; Spouse/Partner; Ionis Pharmaceuticals, Inc.