The Effect of Cellular Glucose Levels on Inotersen-Mediated Target Reduction in in vitro Cell Models

Antisense oligonucleotide (ASO) drugs are a new therapeutic modality to treat rare as well as common diseases. These drugs work to reduce disease by targeting the mRNA of the gene that causes the disease, therefore limiting the proteins that further propagate the signs and symptoms of the disorder. Many people who suffer from more severe diseases, such as Alzheimer’s, Parkinson’s, Duchenne Muscular Dystrophy (DMD), and a wide array of cancers, utilize ASO drugs for treatment, but the drug is also used with those suffering from more common diseases such as diabetes. The efficacy of ASO drugs to silence their mRNA and protein targets under the conditions of common diseases has yet to be investigated, until this study. The study utilized in vitro cell models, HepG2 and HepaRG, to explore the silencing efficacy of the ASO drug, inotersen, in low, normal, and high glucose conditions. Inotersen is an ASO drug that treats hereditary transthyretin-mediated amyloidosis (hATTR), which is a neurodegenerative disorder that causes progressive nervous system damage as well and damages other tissues and organs. The results indicated that high glucose levels decreased inotersen’s ability to reduce its targets, but this can be reversed by lowering the glucose levels through treatment with an antidiabetic drug (metformin) or by knocking down glucose transporters (GLUT2).