Abstract
The novel class of compounds represented by lipid nanoparticle (LNP)-encapsulated siRNA formulations has an enormous potential to target disease, notably of the liver. Endocytosis of LNPs is believed to be mediated by APOE, an important serum protein of lipoprotein homeostasis. APOE polymorphisms affect binding to hepatic receptors and have been associated with development of specific disease. Here, the role of APOE was investigated with regard to the efficacy of Patisiran, the first LNP-siRNA recently approved for clinical use in patients having transthyretin amyloidosis (ATTR amyloidosis). Patisiran was evaluated in the human hepatoma cell line HepG2 after knockdown of APOE. The APOE genotype was determined in ATTR amyloidosis patients treated with Patisiran. TTR knockdown was monitored in consecutive plasma up to week 12. Downregulation of APOE suppressed efficacy of Patisiran in HepG2 cells. TTR levels were found to be robustly reduced (84.7% ± 1%) following Patisiran treatment in patients plasma. Analysis of APOE polymorphisms in ATTR amyloidosis patients revealed three most frequent genotypes E3/3, E3/4 and E3/2. APOE stratification of patients did not show significant differences of TTR plasma concentrations following treatment. Our results suggest that APOE is an important mediator of TTR silencing by Patisiran, however efficacy is independent of the APOE genotype.