Impact on efficacy of target reduction of two FDA-approved ASO drugs by intracellular glucose levels in in vitro cell models.

Abstract

Antisense oligonucleotides (ASOs) have emerged as a new therapeutic modality for the treatment of both rare and common human diseases. A significant proportion of the patient population that may benefit from ASO therapy may also have common diseases, such as diabetes mellitus. The potential influence of prevalent diseases on the effectiveness of ASO drugs in silencing their target mRNAs remains largely unexplored. The present study utilized in vitro cell models to determine the impact on the efficacy of target reduction of two US Food and Drug Administration (FDA)-approved ASO drugs by intracellular glucose levels. Using inotersen and mipomersen as the FDA-approved ASO model drugs, this study demonstrated that a higher intracellular level of glucose resulted in decreased silencing efficacy of target reduction of inotersen and mipomersen in HepG2 cells. Reducing intracellular glucose levels in HepG2 cells, either by knocking down the glucose transporter GLUT2 or by treating with the antidiabetic drug metformin, reversed the decreased silencing efficacy of inotersen and mipomersen. This study brings to light the first indication about the significant impact of intracellular glucose levels on the silencing efficacy of the FDA-approved ASO drugs in an in vitro model.