Targeted delivery of antisense oligonucleotides to pancreatic ß-cells.

Antisense oligonucleotide (ASO) silencing of the expression of disease-associated genes is an attractive novel therapeutic approach, but treatments are limited by the ability to deliver ASOs to cells and tissues. Following systemic administration, ASOs preferentially accumulate in liver and kidney. Among the cell types refractory to ASO uptake is the pancreatic insulin-secreting ß-cell. Here, we show that conjugation of ASOs to a ligand of the glucagon-like peptide-1 receptor (GLP1R) can productively deliver ASO cargo to pancreatic ß-cells both in vitro and in vivo. Ligand-conjugated ASOs silenced target genes in pancreatic islets at doses that did not affect target gene expression in liver or other tissues, indicating enhanced tissue and cell type specificity. This finding has potential to broaden the use of ASO technology, opening up novel therapeutic opportunities, and presents an innovative approach for targeted delivery of ASOs to additional cell types.

Intracellular assembly of VLDL: two major steps in separate cell compartments.

The assembly of very low-density lipoproteins (VLDL) occurs in two major steps. The first step is the co-and post-translational lipidation of apoB, forming pre-VLDL in the rough endoplasmic reticulum. The microsomal triglyceride transfer protein catalyzes this step. In the second step pre-VLDL is converted to bona fide VLDL in a smooth membrane compartment. This step depends on ADP-ribosylation factor 1 and its activation of phospholipase D.