ABSTRACT
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.
Subject(s)
Drug Delivery Systems/methods , Glucagon-Like Peptide-1 Receptor/metabolism , Insulin-Secreting Cells/drug effects , Oligonucleotides, Antisense/administration & dosage , Animals , Forkhead Box Protein O1/genetics , Forkhead Box Protein O1/metabolism , Gene Silencing , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/genetics , HEK293 Cells , Humans , Mice, Inbred C57BL , Mice, Knockout , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/pharmacokinetics , RNA, Long Noncoding/geneticsABSTRACT
Hoarseness is a symptom that is constantly encountered by doctors in primary care. It is the leading symptom in acute laryngitis and is often present as one of the symptoms in, for example, respiratory tract infections, influenza, and bronchitis. For the general practitioner, the infection factor as the cause of hoarseness is so dominant that other possible causes may fail to be taken into consideration. The general practitioner's possibilities for diagnosing the cause of this symptom are largely determined by habit, and by his ability to observe and assess the vocal chords. Examination of the vocal chords is often technically difficult, and patients in whom inspection presents difficulties should be remitted to an ear specialist. Hoarse smokers constitute a special group at risk, and these patients should be remitted for further examinations, if the general practitioner finds it hard to make a complete inspection of the chords. The article also describes an investigation on how hoarseness is handled at a health centre.
