RESUMEN
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.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Oligonucleótidos Antisentido/administración & dosificación , Animales , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Silenciador del Gen , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/genética , Células HEK293 , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Oligonucleótidos Antisentido/química , Oligonucleótidos Antisentido/farmacocinética , ARN Largo no Codificante/genéticaRESUMEN
An approach to the tricyclic core of phomactin A is described via the synthesis of a reduced furanochroman model. Key elements of this study include the use of a highly functionalized 1-oxadecalone derivative as a template for the stereoselective introduction of functionality and a tandem retro aldol-epoxide opening-cyclization sequence for elaboration of the dihydrofuran ring.