Biodistribution of Phosphorothioate-Based Antisense Oligonucleotides in Stabilin Receptor Knock-Out Models.

Phosphorothioate-based antisense oligonucleotides (PS-ASO) are a common class of ASO for therapeutic uses due to their resistance to nucleases and known deposition in human physiological systems. On the molecular level, these ASOs are recognized by several scavenger receptors, including scavenger receptors A and B (SR-A, SR-B) and Stabilin receptors, Stab1 and Stab2. The Stabilins bind and internalize a host of endogenous and exogenous molecules with high endocytic rates and low turnover times. To determine their specific role in the biodistribution of PS-ASOs, we intravascularly injected knockout (KO) mice for Stab1, Stab2 or Stab1Stab2 double KO (DKO). Our results show that each receptor contributes to PS-ASO clearance from the blood and accumulation in liver and spleen, locations where these receptors have the highest levels of expression. Moreover, Stab2 is the primary clearance receptor taking up the bulk of the PS-ASO found in blood. Our conclusion is that Stabilins have a profound effect on the catabolism of PS-ASOs, for which internalization and clearance from the tissue need to be taken into consideration in the design of any therapeutic ASO.