Inotersen

Inotersen (GSK-2998728; ISIS-420915) is a 2'-O-methoxyethyl-modified antisense oligonucleotide and transthyretin (TTR) inhibitor with low genotoxicity. Inotersen triggers RNase H1-mediated degradation by binding to TTR mRNA, thereby effectively reducing the production of both mutant and wild-type transthyretin in the liver. Inotersen significantly reduces amyloid fiber deposition, yet specific toxicities such as inflammation or tumors are observed at high doses in some animal models. Inotersen is used in studies of hereditary transthyretin amyloidosis and the associated polyneuropathy and cardiomyopathy^[1][2][3][4]. In Vitro:Inotersen inhibits the production of TTR in human hepatocellular carcinoma HepG2 cells in in vitro screening assays^[1].
Inotersen specifically and selectively detects anti-Inotersen antibodies in human plasma, with a sensitivity of 6.28 ng/mL, and exhibits strong drug tolerance. It can still recognize 100 ng/mL of anti-Inotersen antibodies even in the presence of 16.0 μg/mL of circulating Inotersen^[2].
Inotersen (10-1000 nM; 48 h) dose-dependently reduces the mRNA and protein levels of transthyretin (TTR) in the human hepatocellular carcinoma cell line HepG2^[3]. In Vivo:Inotersen (25 mg/kg) reduces TTR RNA and protein levels by 90% in human TTR^Ile84Ser transgenic mice, and reduces human TTR mRNA and protein levels by up to 80%, with no adverse effects on the overall health or liver function of mice^[1].
Inotersen (>40 mg/kg/week; 3-6 months) causes mild to moderate mononuclear cell infiltration in the hepatic sinusoids, lymph nodes and injection sites of mice after 3 and 6 months of administration, with no adverse effects on the overall health of the mice^[1].
Inotersen (10-80 mg/kg/w; s.c.; once weekly; 26 weeks) induces mild, dose-dependent changes in serum biochemical parameters and typical microscopic effects in Tg.rasH2 mice^[5].
Subcutaneous administration of Inotersen (0.5-6 mg/kg/w; s.c.; once weekly; 2 years) to Sprague-Dawley rats for up to 2 years induces dose-dependent non-neoplastic effects and subcutaneous fibrosarcomas at injection sites^[5].