Abstract
Revusiran is a 1st-generation short interfering RNA targeting transthyretin conjugated to an N-acetylgalactosamine ligand to facilitate delivery to hepatocytes via uptake by the asialoglycoprotein receptors. Revusiran, in development for the treatment of hereditary transthyretin-mediated amyloidosis, was discontinued after an imbalance in deaths in the “ENDEAVOUR” phase 3 clinical trial. Nonclinical safety assessments included safety pharmacology, acute and repeat-dose toxicity, genotoxicity, and carcinogenicity. There were no effects on cardiovascular or respiratory function in monkeys after single doses of up to 100 mg/kg. No neurological effects were noted in monkeys in repeat-dose studies up to 300 mg/kg. Revusiran was well tolerated in repeat-dose mouse (weekly doses) and rat and monkey (five daily doses followed by weekly doses) toxicity studies. The no observed adverse effect level (NOAEL) in rats was 30 mg/kg based on reversible microscopic changes in liver that were accompanied by correlating elevations in clinical chemistry at higher doses. Dose-limiting toxicity was absent in monkeys, and the NOAEL was 200 mg/kg. There was no evidence of genotoxicity in vitro or in vivo at limit doses or carcinogenicity in a 2-year study in rats at doses up to 100 mg/kg. Overall, these results demonstrate that revusiran had a favorable nonclinical safety profile.
Highlights
RNA interference is a naturally occurring cellular mechanism for regulating gene expression by which a double-stranded short interfering RNA mediates sequence-specific degradation of messenger RNA, leading to the reduced synthesis of the corresponding protein [1]
One approach is to formulate short interfering RNA (siRNA) in intravenously administered lipid nanoparticle formulations that preferentially distribute to hepatocytes via an apolipoprotein E (ApoE)-dependent process mediated by low-density lipoprotein and other ApoE-binding receptors [5]
Another approach utilizes siRNA that is conjugated to a trimer of N-acetylgalactosamine (GalNAc) residues that are recognized by and transported into hepatocytes by asialoglycoprotein receptors (ASGPRs) located on the surface of hepatocytes [4,6]
Summary
RNA interference is a naturally occurring cellular mechanism for regulating gene expression by which a double-stranded short interfering RNA (siRNA) (typically 21–23 nucleosides in length) mediates sequence-specific degradation of messenger RNA (mRNA), leading to the reduced synthesis of the corresponding protein [1]. When synthetic siRNAs are introduced into cells, the guide (or antisense) strand of the siRNA loads into an enzyme complex called the RNA-Inducing Silencing Complex (RISC) This enzyme complex subsequently binds to its complimentary mRNA target sequence, mediating its cleavage by argonaute endonuclease (Ago2) and thereby preventing synthesis of the target protein [2,3]. One approach is to formulate siRNAs in intravenously administered lipid nanoparticle formulations that preferentially distribute to hepatocytes via an apolipoprotein E (ApoE)-dependent process mediated by low-density lipoprotein and other ApoE-binding receptors [5] Another approach utilizes siRNA that is conjugated to a trimer of N-acetylgalactosamine (GalNAc) residues that are recognized by and transported into hepatocytes by asialoglycoprotein receptors (ASGPRs) located on the surface of hepatocytes [4,6]. Once the ligand-receptor complex is internalized, the cargo is released into the endocytic pathway with subsequent engagement with the RISC complex; the ASGPR is rapidly recycled to the cell surface, enabling multiple rounds of cargo uptake and release
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