Table 1.

Preclinical studies on siRNA targeting PCSK9 mRNA.

Study, year	Experimental models	Design	Main Findings
Frank-Kamenetsky et al., 2008 [18]	Mice and rats	Different doses of the lipidoid-formulated siRNA molecule were intravenously injected into mice and rats.	siRNA displayed a dose-response decrease in PCSK9 levels.
			Maximal PCSK9 mRNA silencing of 50–70% at a dose of 5 mg/kg.
			The reduction in mRNA transcription translated into a 30% (for mice) and 60% (for rats) reduction in total plasma cholesterol.
	Non-human primates	Animals were randomized to receive a 5 mg/kg dose of si-RNA molecule or to serve as controls	Inclisiran 5 mg/kg administered as a single dose resulted in a statistically significant decrease in LDL-C starting from day 3.
			LDL-C levels returned to basal values after 14–21 days.
			A significant reduction in plasma PCSK9 concentration was observed.
Unpublished data reported by Fitzgerald et al., 2017 [19]	Non-human primates	Different doses of siRNA (inclisiran) subcutaneously administered to NHPs	With doses greater than 3mg/kg a substantial decrease in PCSK9 ($>$80%) and LDL-C ($\sim$60%) was reported, with nadir effects lasting $>$30 days and a return to basal levels was observed after 90–120 days

LDL-C, low-density lipoprotein cholesterol; NHP, non-human primates; PCSK9, proprotein convertase subtilisin/kexin type 9; siRNA, small interfering RNA.