BioCentury
ARTICLE | Distillery Techniques

Drug delivery

November 6, 2018 7:44 PM UTC

Conjugating ASOs to a GLP-1R agonist construct could enhance the delivery of antisense therapies to pancreatic islet β cells for metabolic diseases. The conjugates consist of 5’-hexylamino ASOs against the selected therapeutic targets linked via disulfide bonds to a GLP-1R agonist construct composed of peptide sequences from human glucagon-like peptide-1 (GLP-1) and Byetta exenatide. This construct targets the conjugates to pancreatic β cells, where disulfide linkers are cleaved intracellularly to release the ASO cargo. In mouse and human pancreatic β islet tissue samples, conjugates containing an ASO against metastasis associated lung adenocarcinoma transcript 1 (MALAT1) or forkhead box O1 (FOXO1) decreased levels of MALAT1 or FOXO1 mRNA compared with unconjugated MALAT1 or FOXO1 ASOs, respectively. Also in the mouse islets, the FOXO1 ASO conjugate decreased FOXO1 protein levels compared with unconjugated FOXO1 ASO. In a genetic mouse model of obesity, subcutaneous administration of the FOXO1 ASO conjugate decreased FOXO1 mRNA and protein levels in pancreatic β islets compared with the unconjugated FOXO1 ASO. Next steps by AstraZeneca plc and Ionis Pharmaceuticals Inc. include testing efficacy and safety of the conjugates in models of Type II diabetes. ...